Thomson Gale 2002 Gale Encyclopedia of Genetic Disorders, Two Volume Set Volume 2 M Z I pdf
The GALE
ENCYCLOPEDIA
of
Genetic
Disorders
The GALE
ENCYCLOPEDIA
of
Genetic
Disorders
VOLUME
2
M-Z
APPENDIX
GLOSSARY
INDEX
S TAC E Y L . B L AC H F O R D, E D I TO R
The GALE
ENCYCLOPEDIA
of GENETIC DISORDERS
STAFF
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ISBN 0-7876-5612-7 (set)
0-7876-5613-5 (Vol. 1)
0-7876-5614-3 (Vol. 2)
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
Library of Congress Cataloging-in-Publication Data
The Gale encyclopedia of genetic disorders / Stacey L. Blachford,
associate editor.
p. cm.
Includes bibliographical references and index.
Summary: Presents nearly four hundred articles describing
genetic disorders, conditions, tests, and treatments, including
high-profile diseases such as Alzheimer’s, breast cancer, and
heart disease.
ISBN 0-7876-5612-7 (set : hardcover : alk.paper
1. Genetic disorders—Encyclopedias, Juvenile. [1. Genetic
disorders—Encyclopedias. 2. Diseases—Encyclopedias.]
I. Blachford, Stacey.
RB155.5 .G35 2001
616’.042’03—dc21
2001040100
M
Machado-Joseph disease see Azorean
disease
I Macular degeneration—
age-related
Definition
Macular degeneration age-related (AMD) is one of
the most common causes of vision loss among adults
over age 55 living in developed countries. It is caused by
the breakdown of the macula, a small spot located in the
back of the eye. The macula allows people to see objects
directly in front of them (called central vision), as well as
fine visual details. People with AMD usually have
blurred central vision, difficulty seeing details and colors,
and they may notice distortion of straight lines.
Description
In order to understand how the macula normally
functions and how it is affected by AMD, it is important
to first understand how the eye works. The eye is made
up of many different types of cells and tissues that all
work together to send images from the environment to
the brain, similar to the way a camera records images.
When light enters the eye, it passes through the lens and
lands on the retina, which is a very thin tissue that lines
the inside of the eye. The retina is actually made up of 10
different layers of specialized cells, which allow the
retina to function similarly to film in a camera, by recording images. The macula is a small, yellow-pigmented
area located at the back of the eye, in the central part of
the retina. The retina contains many specialized cells
called photoreceptors that sense light coming into the eye
and convert it into electrical messages that are then sent
to the brain through the optic nerve. This allows the brain
to “see” the environment.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
The retina contains two types of photoreceptor cells:
rod cells and cone cells. The rod cells are located primarily outside of the macula and they allow for peripheral
(side) and night vision. Most of the photoreceptor cells
inside of the macula, however, are the cone cells, which
are responsible for perceiving color and for viewing
objects directly in front of the eye (central vision). If the
macula is diseased, as in AMD, color vision and central
vision are altered. There are actually two different types
of AMD: Dry AMD and Wet AMD.
Dry AMD
Approximately 90% of individuals with AMD have
dry AMD. This condition is sometimes referred to as
nonexudative, atrophic, or drusenoid macular degeneration. In this form of AMD, some of the layers of retinal
cells (called retinal pigment epithelium, or RPE cells)
near the macula begin to degenerate, or breakdown.
These RPE cells normally help remove waste products
from the cone and rod cells. When the RPE cells are no
longer able to provide this “clean-up” function, fatty
deposits called drusen begin to accumulate, enlarge and
increase in number underneath the macula. The drusen
formation can disrupt the cones and rods in the macula,
causing them to degenerate or die (atrophy). This usually
leads to central and color vision problems for people with
dry AMD. However, some people with drusen deposits
have minimal or no vision loss, and although they may
never develop AMD, they should have regular eye examinations to check for this possibility. Dry AMD is sometimes called “nonexudative”, because even though fatty
drusen deposits form in the eye, people do not have leakage of blood or other fluid (often called exudate) in the
eye. In some cases, dry AMD symptoms remain stable or
worsen slowly. In addition, approximately 10% of people
with dry AMD eventually develop wet AMD.
Wet AMD
Around 10% of patients with AMD have wet AMD.
This form of AMD is also called subretinal neovascular691
Macular degeneration—age-related
KEY TERMS
Central vision—The ability to see objects located
directly in front of the eye. Central vision is necessary for reading and other activities that require
people to focus on objects directly in front of
them.
Choroid—A vascular membrane that covers the
back of the eye between the retina and the sclera
and serves to nourish the retina and absorb scattered light.
Drusen—Fatty deposits that can accumulate
underneath the retina and macula, and sometimes
lead to age-related macular degeneration (AMD).
Drusen formation can disrupt the photoreceptor
cells, which causes central and color vision problems for people with dry AMD.
Genetic heterogeneity—The occurrence of the
same or similar disease, caused by different genes
among different families.
Macula—A small spot located in the back of the
eye that provides central vision and allows people
to see colors and fine visual details.
Multifactorial inheritance—A type of inheritance
pattern where many factors, both genetic and
environmental, contribute to the cause.
Optic nerve—A bundle of nerve fibers that carries
visual messages from the retina in the form of electrical signals to the brain.
Peripheral vision—The ability to see objects that
are not located directly in front of the eye.
Peripheral vision allows people to see objects
located on the side or edge of their field of vision.
Photoreceptors—Specialized cells lining the
innermost layer of the eye that convert light into
electrical messages so that the brain can perceive
the environment. There are two types of photoreceptor cells: rod cells and cone cells. The rod cells
allow for peripheral and night vision. Cone cells
are responsible for perceiving color and for central
vision.
Retina—The light-sensitive layer of tissue in the
back of the eye that receives and transmits visual
signals to the brain through the optic nerve.
Visual acuity—The ability to distinguish details
and shapes of objects.
692
ization, choroidal neovascularization, exudative form or
disciform degeneration. Wet AMD is caused by leakage
of fluid and the formation of abnormal blood vessels
(called “neovascularization”) in a thin tissue layer of the
eye called the choroid. The choroid is located underneath
the retina and the macula, and it normally supplies them
with nutrients and oxygen. When new, delicate blood
vessels form, blood and fluid can leak underneath the
macula, causing vision loss and distortion as the macula
is pushed away from nearby retinal cells. Eventually a
scar (called a disciform scar) can develop underneath the
macula, resulting in severe and irreversible vision loss.
Genetic profile
AMD is considered to be a complex disorder, likely
caused by a combination of genetic and environmental
factors. This type of disorder is caused by multifactorial
inheritance, which means that many factors likely interact with one another and cause the condition to occur. As
implied by the words “age-related”, the aging process is
one of the strongest risk factors for developing AMD. A
number of studies have suggested that genetic susceptibility also plays an important role in the development of
AMD, and it has been estimated that the brothers and sisters of people with AMD are four times more likely to
also develop AMD, compared to other individuals.
Genetic factors
Determining the role that genetic factors play in the
development of AMD is a complicated task for scientists.
Since AMD is not diagnosed until late in life, it is difficult to locate and study large numbers of affected people
in the same family. In addition, although AMD seems to
run in families, there is no clear inheritance pattern
(such as dominant or recessive) observed when examining families. However, many studies have supported the
observation that inheritance plays some role in the development of AMD.
One method scientists use to locate genes that may
increase a person’s chance to develop multifactorial conditions like AMD is to study genes that cause similar conditions. In 1997, this approach helped researchers
identify changes (mutations) in the ATP-binding cassette
transporter, retina-specific (ABCR) gene in people diagnosed with AMD. The process began after genetic
research identified changes in the ABCR gene among
people with an autosomal recessive macular disease
called Stargardt macular dystrophy. This condition is
phenotypically similar to AMD, which means that people
with Stargardt macular dystrophy and AMD have similar
symptoms, such as yellow deposits in the retina and
decreased central vision.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
In 1998, another genetic researcher reported a family in which a unique form of AMD was passed from one
generation to the next. Although most families with
AMD who are studied do not show an obvious inheritance pattern in their family tree, this particular family’s
pedigree showed an apparently autosomal dominant form
of AMD. Autosomal dominant refers to a specific type of
inheritance in which only one copy of a person’s gene
pair (i.e. one allele) needs to have a mutation in order for
it to cause the disease. An affected person with an autosomal dominant condition thus has one allele with a
mutation and one allele that functions properly. There is
a 50% chance for this individual to pass on the allele with
the mutation, and a 50% chance to pass on the working
allele, to each of his or her children.
Genetic testing done on the family reported in 1998
showed that the dominant gene causing AMD in affected
family members was likely located on chromosome
1q25-q31. Although the gene linked to AMD in this family and the ABCR gene are both on chromosome 1, they
are located in different regions of the chromosome. This
indicates that there is genetic heterogeneity among different families with AMD, meaning that different genes
can lead to the same or similar disease among different
families. It is also possible that although one particular
gene may be the main cause of susceptibility for AMD,
other genes and/or environmental factors may help alter
the age of onset of symptoms or types of physical
changes seen by examining the eye. Some studies have
shown that other medical conditions or certain physical
characteristics may be associated with an increased risk
for AMD. Some of these include:
• Heart disease
• High blood pressure
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
• Cataracts
• Farsightedness
• Light skin and eye color
However, not all studies have found a strong relationship between these factors and AMD. Further
research is needed to decipher the role that both genetic
and environmental factors play in the development of this
complex condition.
Environmental factors
Determining the role that environmental factors play
in the development of AMD is an important goal for
researchers. Unlike genetic factors that cannot be controlled, people can often find motivation to change their
behaviors if they are informed about environmental risk
factors that may be within their control. Unfortunately,
identifying environmental factors that clearly increase (or
decrease) the risk for AMD is a challenging task. Several
potential risk factors have been studied. These include:
• Smoking
• High fat/high cholesterol diet
• Ultraviolet (UV) exposure (sunlight)
• Low levels of dietary antioxidant vitamins and minerals
Although research has identified these possible risk
factors, many of the studies have not consistently shown
strong associations between these factors and the development of AMD. This makes it difficult to know the true
significance of any of these risk factors. One exception,
however, is the relationship between smoking and AMD.
As of 1999, at least seven studies consistently found that
smoking is strongly associated with AMD. This is one
more important reason for people to avoid and/or quit
smoking, especially if they have a family history of
AMD. Further research is needed to clarify the significance of the factors listed above so people may be
informed about lifestyle changes that may help decrease
their risk for AMD.
Demographics
Among adults aged 55 and older, AMD is the leading cause of vision loss in developed countries. The
chance to develop AMD increases with age, and although
it usually affects adults during their sixth and seventh
decades of life, it has been seen in some people in their
forties. It is estimated that among people living in developed countries, approximately one in 2,000 are affected
by AMD. By age 75, approximately 30% of people have
early or mild forms of AMD, and roughly 7% have an
advanced form of AMD. Since the number of people in
the United States aged 65 years or older will likely dou693
Macular degeneration—age-related
The ABCR gene maps to chromosome 1p22, and
people who have Stargardt macular dystrophy have mutations in each of their two alleles (gene copies). However,
the researchers who found mutations in the ABCR gene
among people with AMD located only one allele with a
mutation, which likely created an increased susceptibility
to AMD. They concluded that people with an ABCR
gene mutation in one allele could have an increased
chance to develop AMD during their lifetime if they also
had inherited other susceptibility genes, and/or had contact with environmental risk factors. Other scientists tried
to repeat this type of genetic research among people with
AMD in 1999, and were not able to confirm that the
ABCR gene is a strong genetic risk factor for this condition. However, it is possible that the differing research
results may have been caused by different research methods, and further studies will be necessary to understand
the importance of ABCR gene mutations in the development of susceptibility to AMD.
Macular degeneration—age-related
upon whether a person has dry or wet AMD. In addition,
the degree of vision loss and physical symptoms that can
be seen by an eye exam change over time. For example,
people with dry AMD usually develop vision loss very
slowly over a period of many years. Their vision may
change very little from one year to the next, and they usually do not lose central vision completely. However, individuals with wet AMD usually have symptoms that
worsen more quickly and they have a greater risk to
develop severe central vision loss, sometimes in as little
as a two-month period. Since people diagnosed with dry
AMD may go on to develop wet AMD, it is important for
them to take note of any changes in their symptoms and
to report them to their eye care specialist.
A retinal photograph showing macular degeneration.
(Custom Medical Stock Photo, Inc.)
ble between 1999 and 2024, the number of people
affected also should increase. Although AMD occurs in
both sexes, it is slightly more common in women.
The number of people affected with AMD is different in various parts of the world and it varies between different ethnic groups. Some studies suggest that AMD is
more common in Caucasians than in African Americans;
however, other reports suggest the numbers of people
affected in these two groups are similar. Some studies of
AMD among Japanese and other Asian ethnic groups
have shown an increasing number of affected individuals.
Further studies are needed to examine how often AMD
occurs in other ethnic groups as well.
Signs and symptoms
During eye examinations, eye care specialists may
notice physical changes in the retina and macula that
make them suspect the diagnosis of AMD. However,
affected individuals may notice:
• Decreased visual acuity (ability to see details) of both
up-close and distant objects
• Blurred central vision
• Decreased color vision
• Distorted view of lines and shapes
• A blind spot in the visual field
The majority of people with AMD maintain their
peripheral vision. The severity of symptoms depends
694
The physical symptoms of AMD eventually impact
people emotionally. One study published in 1998
reported that people with advanced stages of AMD feel
they have a significantly decreased quality of life. In
addition, they may have a limited ability to perform basic
daily activities due to poor vision, and as a result, they
often suffer psychological distress. Hopefully, improved
treatment and management will eventually change this
trend for affected individuals in the future.
Diagnosis
Eye care specialists use a variety of tests and examination techniques to determine if a person has AMD.
Some of these include:
• Acuity testing—Involves testing vision by determining
a person’s ability to read letters or symbols of various
sizes on an “eye chart” from a precise distance away
with specific lighting present.
• Color testing—Assesses the ability of the cone cells to
recognize colors by using special pictures made up of
dots of colors that are arranged in specific patterns.
• Amsler grid testing—Involves the use of a grid printed
on a piece of paper that helps determine the health of
the macula, by allowing people to notice whether they
have decreased central vision, distorted vision, or blind
spots.
• Fluorescein angiography—Involves the use of a fluorescent dye, injected into the bloodstream, in order to
look closely at the blood supply and blood vessels near
the macula. The dye allows the eye specialist to examine and photograph the retina and macula to check for
signs of wet AMD (i.e. abnormal blood vessel formation or blood leakage).
As of 2001, there are no genetic tests readily available to help diagnose AMD. Genetic research in the coming years will hopefully help scientists determine the
genetic basis of AMD. This could help diagnose people
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
• Magnifying lenses
• Telescopes
• Specialized prisms
• Large print books
• Reading machines
Treatment and management
• Computer programs that talk or enlarge printed information
Treatment
People with AMD may also find it useful to meet
with low-vision specialists who can help them adapt to
new lifestyle changes that may assist with daily living.
Eye care specialists can help people locate low-vision
specialists. There are also a number of nationwide and
international support groups available that provide education and support for individuals and families affected
by AMD.
There is no universal treatment available to cure
either wet or dry forms of AMD. However, some people
with wet AMD can benefit from laser photocoagulation
therapy. This treatment involves the use of light rays from
a laser to destroy the abnormal blood vessels that form
beneath the retina and macula and prevent further leakage of blood and fluid. Previously lost vision cannot be
restored with this treatment, and the laser can unfortunately damage healthy tissue as well, causing further loss
of vision.
In April 2000, the FDA approved the use of a lightactivated drug called Visudyne to help treat people with
wet AMD. Visudyne is a medication that is injected into
the bloodstream, and it specifically attaches to the abnormal blood vessels present under the macula in people
with AMD. When light rays from a laser land on the
blood vessels, the Visudyne is activated and can destroy
the abnormal vessels, while causing very little damage to
nearby healthy tissues. Although long term studies are
needed to determine the safety and usefulness of this
medication beyond two years, early reports find it an
effective way to reduce further vision loss.
Researchers have been trying to identify useful treatments for dry AMD as well. Laser photocoagulation
treatments are not effective for dry AMD since people
with this form do not have abnormal blood or fluid leakage. Although many drugs have been tested, most have
not improved visual acuity. However, one study published in October 2000, reported that people with dry
AMD who received a medication called Iloprost over a
six-month period noted improvements in visual acuity,
daily living activities and overall quality of life. Followup studies will be needed to determine how safe and useful this medication will be over time.
Management
Although no treatments can cure AMD, a number of
special devices can help people make the most of their
remaining vision. Some of these include:
• Walking canes
• Guide dogs
• Audiotapes
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Prognosis
People can live many years with AMD, although the
physical symptoms and emotional side effects often
change over time. The vision problems caused by dry
AMD typically worsen slowly over a period of years, and
people often retain the ability to read. However, for people who develop wet AMD, the chance to suddenly
develop severe loss of central vision is much greater.
Regular monitoring of vision by people with AMD (using
an Amsler grid) and by their eye care specialists, may
allow for early treatment of leaky blood vessels, therefore
reducing the chance for severe vision loss. As physical
symptoms worsen, people are more likely to suffer emotionally due to decreasing quality of life and independence. However, many low-vision devices and various
support groups can often provide much needed assistance
to help maintain and/or improve quality of life.
Resources
BOOKS
D’Amato, Robert, and Joan Snyder. Macular Degeneration:
The Latest Scientific Discoveries and Treatments for
Preserving Your Sight. New York: Walker & Co., 2000.
Solomon, Yale, and Jonathan D. Solomon. Overcoming
Macular Degeneration: A Guide to Seeing Beyond the
Clouds. New York: Morrow/Avon, 2000.
PERIODICALS
Bressler, Neil M., and James P. Gills. “Age related macular
degeneration.” British Medical Journal 321, no. 7274
(December 2000): 1425–1427.
Fong, Donald S. “Age-Related Macular Degeneration: Update
for Primary Care.” American Family Physician 61, no. 10
(May 2000): 3035–3042.
“Macular degeneration.” Harvard Women’s Health Watch 6, no.
2 (October 1998): 2–3.
695
Macular degeneration—age-related
with increased susceptibility before they have symptoms,
so they may benefit from early diagnosis, management
and/or treatment. This knowledge may also allow people
who are at a genetically increased risk for AMD to avoid
environmental risk factors and thus preserve or prolong
healthy vision.
Major histocompatibility complex
“Researchers set sights on vision disease.” Harvard Health
Letter 23, no.10 (August 1998):4–5.
“Self-test for macular degeneration.” Consumer Reports on
Health 12, no.12 (December 2000): 2.
ORGANIZATIONS
AMD Alliance International. PO Box 550385, Atlanta, GA
30355. (877) 263-7171. ⬍http://www.amdalliance.org⬎.
American Macular Degeneration Foundation. PO Box 515,
Northampton, MA 01061-0515. (413) 268-7660.
⬍http://www.macular.org⬎.
Foundation Fighting Blindness Executive Plaza 1, Suite 800,
11350 McCormick Rd., Hunt Valley, MD 21031. (888)
394-3937. ⬍http://www.blindness.org⬎.
Macular Degeneration Foundation. PO Box 9752, San Jose, CA
95157. (888) 633-3937. ⬍http://www.eyesight.org⬎.
Retina International. Ausstellungsstrasse 36, Zürich, CH-8005.
Switzerland (⫹41 1 444 10 77). ⬍http://www.retinainternational.org⬎.
Pamela J. Nutting, MS, CGC
Madelung deformity see Leri-Weill
dyschondrosteosis
Maffuci disease see Chondrosarcoma
I Major histocompatibility
complex
Definition
In humans, the proteins coded by the genes of the
major histocompatibility complex (MHC) include human
leukocyte antigens (HLA), as well as other proteins.
HLA proteins are present on the surface of most of the
body’s cells and are important in helping the immune
system distinguish ‘self’ from ‘non-self’.
Description
The function and importance of MHC is best understood in the context of a basic understanding of the function of the immune system. The immune system is
responsible for distinguishing ‘self’ from ‘non-self’, primarily with the goal of eliminating foreign organisms
and other invaders that can result in disease. There are
several levels of defense characterized by the various
stages and types of immune response.
Natural immunity
When a foreign organism enters the body, it is
encountered by the components of the body’s natural
696
immunity. Natural immunity is the non-specific first-line
of defense carried out by phagocytes, natural killer cells,
and components of the complement system. Phagocytes
are specialized white blood cells capable of engulfing
and killing an organism. Natural killer cells are also specialized white blood cells that respond to cancer cells
and certain viral infections. The complement system is a
group of proteins called the class III MHC that attack
antigens. Antigens consist of any molecule capable of
triggering an immune response. Although this list is not
exhaustive, antigens can be derived from toxins, protein,
carbohydrates, DNA, or other molecules from viruses,
bacteria, cellular parasites, or cancer cells.
Acquired immunity
The natural immune response will hold an infection
at bay as the next line of defense mobilizes through
acquired, or specific immunity. This specialized type of
immunity is usually needed to eliminate an infection and
is dependent on the role of the proteins of the major histocompatibility complex. There are two types of acquired
immunity. Humoral immunity is important in fighting
infections outside the body’s cells, such as those caused
by bacteria and certain viruses. Other types of viruses
and parasites that invade the cells are better fought by
cellular immunity. The major players in acquired immunity are the antigen-presenting cells (APCs), B-cells,
their secreted antibodies, and the T-cells. Their functions
are described in detail below.
Humoral immunity
In humoral immunity, antigen-presenting cells,
including some B-cells, engulf and break down foreign
organisms. Antigens from these foreign organisms are
then brought to the outside surface of the antigen-presenting cells and presented in conjunction with class II
MHC proteins. The helper T-cells recognize the antigen
presented in this way and release cytokines, proteins that
signal B-cells to take further action. B-cells are specialized white blood cells that mature in the bone marrow.
Through the process of maturation, each B-cell develops
the ability to recognize and respond to a specific antigen.
Helper T-cells aid in stimulating the few B-cells that can
recognize a particular foreign antigen. B-cells that are
stimulated in this way develop into plasma cells, which
secrete antibodies specific to the recognized antigen.
Antibodies are proteins that are present in the circulation,
as well as being bound to the surface of B-cells. They can
destroy the foreign organism from which the antigen
came. Destruction occurs either directly, or by ‘tagging’
the organism, which will then be more easily recognized
and targeted by phagocytes and complement proteins.
Some of the stimulated B-cells go on to become memory
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Cellular immunity
Another type of acquired immunity involves killer Tcells and is termed celluar immunity. T-cells go through
a process of maturation in the organ called the thymus, in
which T-cells that recognize ‘self’ antigens are eliminated. Each remaining T-cell has the ability to recognize
a single, specific, ‘non-self’ antigen that the body may
encounter. Although the names are similar, killer T-cells
are unlike the non-specific natural killer cells in that they
are specific in their action. Some viruses and parasites
quickly invade the body’s cells, where they are ‘hidden’
from antibodies. Small pieces of proteins from these
invading viruses or parasites are presented on the surface
of infected cells in conjunction with class I MHC proteins, which are present on the surface of most all of the
body’s cells. Killer T-cells can recognize antigen bound
to class I MHC in this way, and they are prompted to
release chemicals that act directly to kill the infected cell.
There is also a role for helper T-cells and antigen-presenting cells in cellular immunity. Helper T-cells release
cytokines, as in the humoral response, and the cytokines
stimulate killer T-cells to multiply. Antigen-presenting
cells carry foreign antigen to places in the body where
additional killer T-cells can be alerted and recruited.
The major histocompatibility complex clearly performs an important role in functioning of the immune
system. Related to this role in disease immunity, MHC is
important in organ and tissue transplantation, as well as
playing a role in susceptibility to certain diseases. HLA
typing can also provide important information in parentage, forensic, and anthropologic studies. These various
roles and the practical applications of HLA typing are
discussed in greater detail below.
Genetic profile
Present on chromosome 6, the major histocompatibility complex consists of more than 70 genes, classified
into class I, II, and III MHC. There are multiple alleles,
or forms, of each HLA gene. These alleles are expressed
as proteins on the surface of various cells in a co-dominant manner. This diversity is important in maintaining
an effective system of specific immunity. Altogether, the
MHC genes span a region that is four million base pairs
in length. Although this is a large region, 99% of the time
these closely-linked genes are transmitted to the next
generation as a unit of MHC alleles on each chromosome
6. This unit is called a haplotype.
Class I
Class I MHC genes include HLA-A, HLA-B, and
HLA-C. Class I MHC are expressed on the surface of
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
almost all cells. They are important for displaying antigen
from viruses or parasites to killer T-cells in cellular immunity. Class I MHC is also particularly important in organ
and tissue rejection following transplantation. In addition
to the portion of class I MHC coded by the genes on chromosome 6, each class I MHC protein also contains a small,
non-variable protein component called beta-2 microglobulin coded by a gene on chromosome 15. Class I HLA
genes are highly polymorphic, meaning there are multiple
forms, or alleles, of each gene. There are at least 57 HLAA alleles, 111 HLA-B alleles, and 34 HLA-C alleles.
Class II
Class II MHC genes include HLA-DP, HLA-DQ,
and HLA-DR. Class II MHC are particularly important in
humoral immunity. They present foreign antigen to
helper T-cells, which stimulate B-cells to elicit an antibody response. Class II MHC is only present on antigen
presenting cells, including phagocytes and B-cells. Like
class I MHC, there are hundreds of alleles that make up
the class II HLA gene pool.
Class III
Class III MHC genes include the complement system (i.e. C2, C4a, C4b, Bf). Complement proteins help to
activate and maintain the inflammatory process of an
immune response.
Demographics
There is significant variability of the frequencies of
HLA alleles among ethnic groups. This is reflected in
anthropologic studies attempting to use HLA-types to
determine patterns of migration and evolutionary relationships of peoples of various ethnicity. Ethnic variation
is also reflected in studies of HLA-associated diseases.
Generally speaking, populations that have been subject to
significant patterns of migration and assimilation with
other populations tend to have a more diverse HLA gene
pool. For example, it is unlikely that two unrelated individuals of African ancestry would have matched HLA
types. Conversely, populations that have been isolated
due to geography, cultural practices, and other historical
influences may display a less diverse pool of HLA types,
making it more likely for two unrelated individuals to be
HLA-matched.
Testing
Organ and tissue transplantation
There is a role for HLA typing of individuals in various settings. Most commonly, HLA typing is used to
establish if an organ or tissue donor is appropriately
matched to the recipient for key HLA types, so as not to
697
Major histocompatibility complex
cells, which are able to mount an even faster response if
the antigen is encountered a second time.
Disease susceptibility
There is an established relationship between the
inheritance of certain HLA types and susceptibility to
specific diseases. Most commonly, these are diseases that
are thought to be autoimmune in nature. Autoimmune
diseases are those characterized by inflammatory reactions that occur as a result of the immune system mistakenly attacking ‘self’ tissues. The basis of the HLA
association is not well understood, although there are
some hypotheses. Most autoimmune diseases are characterized by the expression of class II MHC on cells of the
body that do not normally express these proteins. This
may confuse the killer T-cells, which respond inappropriately by attacking these cells. Molecular mimicry is
another hypothesis. Certain HLA types may ‘look like’
antigen from foreign organisms. If an individual is
infected by such a foreign virus or bacteria, the immune
system mounts a response against the invader. However,
there may be a ‘cross-reaction’ with cells displaying the
HLA type that is mistaken for foreign antigen. Whatever
the underlying mechanism, certain HLA-types are known
factors that increase the relative risk for developing specific autoimmune diseases. For example, individuals who
carry the HLA B-27 allele have a relative risk of 77–90
for developing ankylosing spondylitis—meaning such an
individual has a 77- to 90-fold chance of developing this
form of spinal and pelvic arthritis, as compared to someone in the general population. Selected associations are
listed below, together with the approximate corresponding relative risk of disease.
In addition to autoimmune disease, HLA-type less
commonly plays a role in susceptibility to other diseases,
including cancer, certain infectious diseases, and metabolic diseases. Conversely, some HLA-types confer a
protective advantage for certain types of infectious disease. In addition, there are rare immune deficiency diseases that result from inherited mutations of the genes of
components of the major histocompatibility complex.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
TABLE 1
HLA disease associations
Disease
MHC allele
Approximate relative risk
Ankylosing spondylitis
Celiac disease
Diabetes, Type 1
Diabetes, Type 1
Diabetes, Type 1
Graves disease
Hemochromatosis
Lupus
Multiple sclerosis
Myasthenia gravis
Psoriasis vulgaris
Rheumatoid arthritis
B27
DR3 + DR7
DR3
DR4
DR3 + DR4
DR3
A3
DR3
DR2
B8
Cw6
DR4
77–90
5–10
5
5–7
20–40
5
6–20
1–3
2–4
2.5–4
8
3–6
The relative risks indicated in this table refer to the increased chance of a
patient with an MHC allele to develop a disorder as compared to an
individual without one. For example, a patient with DR4 is three to six
times more likely to have rheumatoid arthritis and five to seven times
more likely to develop type 1 diabetes than an individual without the DR4
allele.
Parentage
Among other tests, HLA typing can sometimes be
used to determine parentage, most commonly paternity, of a child. This type of testing is not generally
done for medical reasons, but rather for social or legal
reasons.
Forensics
HLA-typing can provide valuable DNA-based evidence contributing to the determination of identity in
criminal cases. This technology has been used in domestic criminal trials. Additionally, it is a technology that has
been applied internationally in the human-rights arena.
For example, HLA-typing had an application in
Argentina following a military dictatorship that ended in
1983. The period under the dictatorship was marked by
the murder and disappearance of thousands who were
known or suspected of opposing the regime’s practices.
Children of the disappeared were often ‘adopted’ by military officials and others. HLA-typing was one tool used
to determine non-parentage and return children to their
biological families.
Anthropologic studies
HLA-typing has proved to be an invaluable tool in
the study of the evolutionary origins of human populations. This information, in turn, contributes to an under699
Major histocompatibility complex
elicit a rejection reaction in which the recipient’s immune
system attacks the donor tissue. In the special case of
bone marrow transplantation, the risk is for graft-versushost disease (GVHD), as opposed to tissue rejection.
Because the bone marrow contains the cells of the
immune system, the recipient effectively receives the
donor’s immune system. If the donor immune system
recognizes the recipient’s tissues as foreign, it may begin
to attack, causing the inflammation and other complications of GVHD. As advances occur in transplantation
medicine, HLA typing for transplantation occurs with
increasing frequency and in various settings.
Malignant hyperthermia
standing of cultural and linguistic relationships and practices among and within various ethnic groups.
Resources
BOOKS
Abbas, A.K., et al. Cellular and Molecular Immunology.
Philadelphia: W.B. Saunders, 1991.
Doherty, D.G., and G.T. Nepom. “The human major histocompatibility complex and disease susceptibility.” In Emery
and Rimoin’s Principles and Practice of Medical
Genetics. 3rd ed. Ed. D.L. Rimoin, J.M. Connor, and R.E.
Pyeritz, 479–504. New York: Churchill Livingston, 1997.
Jorde L.B., et al. “Immunogenetics.” In Medical Genetics. 2nd
ed. St. Louis: Moseby, 1999.
PERIODICALS
Diamond, J.M. “Abducted orphans identified by grandpaternity
testing.” Nature 327 (1987): 552–53.
Svejgaard, A., et al. “Associations between HLA and disease
with notes on additional associations between a ‘new’
immunogenetic marker and rheumatoid arthritis.” HLA
and Disease—The Molecular Basis. Alfred Benzon
Symposium. 40 (1997): 301–13.
Trachtenberg, E.A., and H.A. Erlich. “DNA-based HLA typing
for cord blood stem cell transplantation.” Journal of
Hematotherapy 5 (1996): 295–300.
WEBSITES
“Biology of the immune system.” The Merck Manual
⬍http://www.merck.com/pubs/mmanual_home/sec16/176
.htm⬎.
Jennifer Denise Bojanowski, MS, CGC
Male turner syndrome see Noonan
syndrome
Malignant fever see Malignant
hyperthermia
Malignant hyperpyrexia see Malignant
hyperthermia
perature (i.e. hyperthermia). Although MH can usually be
treated successfully, it sometimes leads to long-term
physical illness or death. Research has identified a number of genetic regions that may be linked to an increased
MH susceptibility.
Description
Unusual response to anesthesia was first reported in
a medical journal during the early 1960s, when physicians described a young man in need of urgent surgery for
a serious injury. He was very nervous about exposure to
anesthesia, since he had 10 close relatives who died during or just after surgeries that required anesthesia. The
patient himself became very ill and developed a high temperature after he was given anesthesia. During the next
decade, more cases of similar reactions to anesthesia
were reported, and specialists began using the term
malignant hyperthermia to describe the newly recognized
condition. The word hyperthermia was used because people with this condition often rapidly develop a very high
body temperature. The word malignant referred to the
fact that the majority (70–80%) of affected individuals
died. The high death rate in the 1960s occurred because
the underlying cause of the condition was not understood,
nor was there any known treatment (other than basically
trying to cool the person’s body with ice).
Increased awareness of malignant hyperthermia and
scientific research during the following decades
improved medical professionals’ knowledge about what
causes the condition, how it affects people, and how it
should be treated. MH can be thought of as a chain reaction that is triggered when a person with MH susceptibility is exposed to specific drugs commonly used for
anesthesia and muscle relaxation.
Triggering drugs that may lead to malignant hyperthermia include:
• halothane
• enflurane
• isoflurane
I Malignant hyperthermia
• sevoflurane
Definition
• methoxyflurane
Malignant hyperthermia (MH) is a condition that
causes a number of physical changes to occur among
genetically susceptible individuals when they are
exposed to a particular muscle relaxant or certain types of
medications used for anesthesia. The changes may
include increased rate of breathing, increased heart rate,
muscle stiffness, and significantly increased body tem700
• desflurane
• ether
• succinylcholine
Once an MH susceptible person is exposed to one or
more of these anesthesia drugs, they can present with a
variety of signs. One of the first clues that a person is susceptible to MH is often seen when they are given a musGALE ENCYCLOPEDIA OF GENETIC DISORDERS
The series of events that occur after exposure to trigger drugs is activated by an abnormally high amount of
calcium inside muscle cells. This is due to changes in the
chemical reactions that control muscle contraction and
the production of energy. Calcium is normally stored in
an area called the sarcoplasmic reticulum, which is a system of tiny tubes located inside muscle cells. This system
of tubes allows muscles to contract (by releasing calcium) and to relax (by storing calcium) in muscle cells.
Calcium also plays an important role in the production of
energy inside cells (i.e. metabolism). There are at least
three important proteins located in (or nearby) the sarcoplasmic reticulum that control how much calcium is
released into muscle cells and thus help muscles contract.
One of these proteins is a “calcium release channel” protein that has been named the ryanodine receptor protein,
or RYR. This protein (as well as the gene that tells the
body how to make it) has been an important area of
research. For some reason, when people with MH susceptibility are exposed to a trigger drug, they can develop
very high levels of calcium in their muscle cells. The trigger drugs presumably stimulate the proteins that control
the release of calcium, causing them to create very high
levels of calcium in muscle cells. This abnormally high
calcium level then leads to increased metabolism, muscle
stiffness, and the other symptoms of MH.
The amount of time that passes between the exposure to trigger drugs and the appearance of the first symptoms of MH varies between different people. Symptoms
begin within 10 minutes for some individuals, although
several hours may pass before symptoms appear in others. This means that some people do not show signs of
MH until they have left the operating room and are recovering from surgery. In addition, some individuals who
inherit MH susceptibility may be exposed to trigger
drugs numerous times during multiple surgeries without
any complications. However, they still have an increased
risk to develop an MH episode during future exposures.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
KEY TERMS
Anesthesia—Lack of normal sensation (especially
to pain) brought on by medications just prior to
surgery or other medical procedures.
Genetic heterogeneity—The occurrence of the
same or similar disease, caused by different genes
among different families.
Hyperthermia—Body temperature that is much
higher than normal (i.e. higher than 98.6°F).
Masseter spasm—Stiffening of the jaw muscles.
Often one of the first symptoms of malignant
hyperthermia susceptibility that occurs after exposure to a trigger drug.
Metabolism—The total combination of all of the
chemical processes that occur within cells and tissues of a living body.
Sarcoplasmic reticulum—A system of tiny tubes
located inside muscle cells that allow muscles to
contract and relax by alternatively releasing and
storing calcium.
Trigger drugs—Specific drugs used for muscle
relaxation and anesthesia that can trigger an
episode of malignant hyperthermia in a susceptible person. The trigger drugs include halothane,
enflurane, isoflurane, sevoflurane, desflurane,
methoxyflurane, ether, and succinylcholine.
This means that people who have an increased risk for
MH susceptibility due to their family history cannot presume they are not at risk simply because they previously
had successful surgeries. Although MH was frequently a
fatal condition in the past, a drug called dantrolene
sodium became available in 1979, which greatly
decreased the rate of both death and disability.
Genetic profile
Susceptibility to MH is generally considered to be
inherited as an autosomal dominant trait. “Autosomal”
means that males and females are equally likely to be
affected. “Dominant” refers to a specific type of inheritance in which only one copy of a person’s gene pair
needs to be changed in order for the susceptibility to be
present. In this situation, an individual susceptible to MH
receives a changed copy of the same gene from one parent (who is also susceptible to MH). This means that a
person with MH susceptibility has one copy of the
changed gene and one copy of the gene that works well.
The chance that a parent with MH susceptibility will
701
Malignant hyperthermia
cle relaxant called succinyl choline. This drug generally
causes some stiffness in the masseter (jaw) muscles in
most people. However, individuals with MH susceptibility can develop a much more severe form of jaw stiffness
called masseter spasm when they receive this drug. They
may develop muscle stiffness in other parts of their bodies as well. When exposed to any of the trigger drugs
listed above (inhalants for anesthesia), people with MH
susceptibility can develop an increased rate of metabolism in the cells of their body, resulting in rapid breathing, rapid heartbeat, high body temperature (over 110°F),
muscle stiffness, and muscle breakdown. If these signs
are not recognized, treated, or able to be controlled, brain
damage or death can occur due to internal bleeding, heart
failure, or failure other organs.
Malignant hyperthermia
have a child who is also susceptible is 50% for each pregnancy. The same parent would also have a 50% chance to
have a non-susceptible child with each pregnancy.
It is not unusual for people to not know they inherited a genetic change that causes MH susceptibility. This
is because they typically do not show symptoms unless
they are exposed to a specific muscle relaxant or certain
anesthetics, which may not be needed by every person
during his or her lifetime. In addition, people who inherit
MH susceptibility do not always develop a reaction to
trigger drugs, which means
ENCYCLOPEDIA
of
Genetic
Disorders
The GALE
ENCYCLOPEDIA
of
Genetic
Disorders
VOLUME
2
M-Z
APPENDIX
GLOSSARY
INDEX
S TAC E Y L . B L AC H F O R D, E D I TO R
The GALE
ENCYCLOPEDIA
of GENETIC DISORDERS
STAFF
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ISBN 0-7876-5612-7 (set)
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0-7876-5614-3 (Vol. 2)
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
Library of Congress Cataloging-in-Publication Data
The Gale encyclopedia of genetic disorders / Stacey L. Blachford,
associate editor.
p. cm.
Includes bibliographical references and index.
Summary: Presents nearly four hundred articles describing
genetic disorders, conditions, tests, and treatments, including
high-profile diseases such as Alzheimer’s, breast cancer, and
heart disease.
ISBN 0-7876-5612-7 (set : hardcover : alk.paper
1. Genetic disorders—Encyclopedias, Juvenile. [1. Genetic
disorders—Encyclopedias. 2. Diseases—Encyclopedias.]
I. Blachford, Stacey.
RB155.5 .G35 2001
616’.042’03—dc21
2001040100
M
Machado-Joseph disease see Azorean
disease
I Macular degeneration—
age-related
Definition
Macular degeneration age-related (AMD) is one of
the most common causes of vision loss among adults
over age 55 living in developed countries. It is caused by
the breakdown of the macula, a small spot located in the
back of the eye. The macula allows people to see objects
directly in front of them (called central vision), as well as
fine visual details. People with AMD usually have
blurred central vision, difficulty seeing details and colors,
and they may notice distortion of straight lines.
Description
In order to understand how the macula normally
functions and how it is affected by AMD, it is important
to first understand how the eye works. The eye is made
up of many different types of cells and tissues that all
work together to send images from the environment to
the brain, similar to the way a camera records images.
When light enters the eye, it passes through the lens and
lands on the retina, which is a very thin tissue that lines
the inside of the eye. The retina is actually made up of 10
different layers of specialized cells, which allow the
retina to function similarly to film in a camera, by recording images. The macula is a small, yellow-pigmented
area located at the back of the eye, in the central part of
the retina. The retina contains many specialized cells
called photoreceptors that sense light coming into the eye
and convert it into electrical messages that are then sent
to the brain through the optic nerve. This allows the brain
to “see” the environment.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
The retina contains two types of photoreceptor cells:
rod cells and cone cells. The rod cells are located primarily outside of the macula and they allow for peripheral
(side) and night vision. Most of the photoreceptor cells
inside of the macula, however, are the cone cells, which
are responsible for perceiving color and for viewing
objects directly in front of the eye (central vision). If the
macula is diseased, as in AMD, color vision and central
vision are altered. There are actually two different types
of AMD: Dry AMD and Wet AMD.
Dry AMD
Approximately 90% of individuals with AMD have
dry AMD. This condition is sometimes referred to as
nonexudative, atrophic, or drusenoid macular degeneration. In this form of AMD, some of the layers of retinal
cells (called retinal pigment epithelium, or RPE cells)
near the macula begin to degenerate, or breakdown.
These RPE cells normally help remove waste products
from the cone and rod cells. When the RPE cells are no
longer able to provide this “clean-up” function, fatty
deposits called drusen begin to accumulate, enlarge and
increase in number underneath the macula. The drusen
formation can disrupt the cones and rods in the macula,
causing them to degenerate or die (atrophy). This usually
leads to central and color vision problems for people with
dry AMD. However, some people with drusen deposits
have minimal or no vision loss, and although they may
never develop AMD, they should have regular eye examinations to check for this possibility. Dry AMD is sometimes called “nonexudative”, because even though fatty
drusen deposits form in the eye, people do not have leakage of blood or other fluid (often called exudate) in the
eye. In some cases, dry AMD symptoms remain stable or
worsen slowly. In addition, approximately 10% of people
with dry AMD eventually develop wet AMD.
Wet AMD
Around 10% of patients with AMD have wet AMD.
This form of AMD is also called subretinal neovascular691
Macular degeneration—age-related
KEY TERMS
Central vision—The ability to see objects located
directly in front of the eye. Central vision is necessary for reading and other activities that require
people to focus on objects directly in front of
them.
Choroid—A vascular membrane that covers the
back of the eye between the retina and the sclera
and serves to nourish the retina and absorb scattered light.
Drusen—Fatty deposits that can accumulate
underneath the retina and macula, and sometimes
lead to age-related macular degeneration (AMD).
Drusen formation can disrupt the photoreceptor
cells, which causes central and color vision problems for people with dry AMD.
Genetic heterogeneity—The occurrence of the
same or similar disease, caused by different genes
among different families.
Macula—A small spot located in the back of the
eye that provides central vision and allows people
to see colors and fine visual details.
Multifactorial inheritance—A type of inheritance
pattern where many factors, both genetic and
environmental, contribute to the cause.
Optic nerve—A bundle of nerve fibers that carries
visual messages from the retina in the form of electrical signals to the brain.
Peripheral vision—The ability to see objects that
are not located directly in front of the eye.
Peripheral vision allows people to see objects
located on the side or edge of their field of vision.
Photoreceptors—Specialized cells lining the
innermost layer of the eye that convert light into
electrical messages so that the brain can perceive
the environment. There are two types of photoreceptor cells: rod cells and cone cells. The rod cells
allow for peripheral and night vision. Cone cells
are responsible for perceiving color and for central
vision.
Retina—The light-sensitive layer of tissue in the
back of the eye that receives and transmits visual
signals to the brain through the optic nerve.
Visual acuity—The ability to distinguish details
and shapes of objects.
692
ization, choroidal neovascularization, exudative form or
disciform degeneration. Wet AMD is caused by leakage
of fluid and the formation of abnormal blood vessels
(called “neovascularization”) in a thin tissue layer of the
eye called the choroid. The choroid is located underneath
the retina and the macula, and it normally supplies them
with nutrients and oxygen. When new, delicate blood
vessels form, blood and fluid can leak underneath the
macula, causing vision loss and distortion as the macula
is pushed away from nearby retinal cells. Eventually a
scar (called a disciform scar) can develop underneath the
macula, resulting in severe and irreversible vision loss.
Genetic profile
AMD is considered to be a complex disorder, likely
caused by a combination of genetic and environmental
factors. This type of disorder is caused by multifactorial
inheritance, which means that many factors likely interact with one another and cause the condition to occur. As
implied by the words “age-related”, the aging process is
one of the strongest risk factors for developing AMD. A
number of studies have suggested that genetic susceptibility also plays an important role in the development of
AMD, and it has been estimated that the brothers and sisters of people with AMD are four times more likely to
also develop AMD, compared to other individuals.
Genetic factors
Determining the role that genetic factors play in the
development of AMD is a complicated task for scientists.
Since AMD is not diagnosed until late in life, it is difficult to locate and study large numbers of affected people
in the same family. In addition, although AMD seems to
run in families, there is no clear inheritance pattern
(such as dominant or recessive) observed when examining families. However, many studies have supported the
observation that inheritance plays some role in the development of AMD.
One method scientists use to locate genes that may
increase a person’s chance to develop multifactorial conditions like AMD is to study genes that cause similar conditions. In 1997, this approach helped researchers
identify changes (mutations) in the ATP-binding cassette
transporter, retina-specific (ABCR) gene in people diagnosed with AMD. The process began after genetic
research identified changes in the ABCR gene among
people with an autosomal recessive macular disease
called Stargardt macular dystrophy. This condition is
phenotypically similar to AMD, which means that people
with Stargardt macular dystrophy and AMD have similar
symptoms, such as yellow deposits in the retina and
decreased central vision.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
In 1998, another genetic researcher reported a family in which a unique form of AMD was passed from one
generation to the next. Although most families with
AMD who are studied do not show an obvious inheritance pattern in their family tree, this particular family’s
pedigree showed an apparently autosomal dominant form
of AMD. Autosomal dominant refers to a specific type of
inheritance in which only one copy of a person’s gene
pair (i.e. one allele) needs to have a mutation in order for
it to cause the disease. An affected person with an autosomal dominant condition thus has one allele with a
mutation and one allele that functions properly. There is
a 50% chance for this individual to pass on the allele with
the mutation, and a 50% chance to pass on the working
allele, to each of his or her children.
Genetic testing done on the family reported in 1998
showed that the dominant gene causing AMD in affected
family members was likely located on chromosome
1q25-q31. Although the gene linked to AMD in this family and the ABCR gene are both on chromosome 1, they
are located in different regions of the chromosome. This
indicates that there is genetic heterogeneity among different families with AMD, meaning that different genes
can lead to the same or similar disease among different
families. It is also possible that although one particular
gene may be the main cause of susceptibility for AMD,
other genes and/or environmental factors may help alter
the age of onset of symptoms or types of physical
changes seen by examining the eye. Some studies have
shown that other medical conditions or certain physical
characteristics may be associated with an increased risk
for AMD. Some of these include:
• Heart disease
• High blood pressure
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
• Cataracts
• Farsightedness
• Light skin and eye color
However, not all studies have found a strong relationship between these factors and AMD. Further
research is needed to decipher the role that both genetic
and environmental factors play in the development of this
complex condition.
Environmental factors
Determining the role that environmental factors play
in the development of AMD is an important goal for
researchers. Unlike genetic factors that cannot be controlled, people can often find motivation to change their
behaviors if they are informed about environmental risk
factors that may be within their control. Unfortunately,
identifying environmental factors that clearly increase (or
decrease) the risk for AMD is a challenging task. Several
potential risk factors have been studied. These include:
• Smoking
• High fat/high cholesterol diet
• Ultraviolet (UV) exposure (sunlight)
• Low levels of dietary antioxidant vitamins and minerals
Although research has identified these possible risk
factors, many of the studies have not consistently shown
strong associations between these factors and the development of AMD. This makes it difficult to know the true
significance of any of these risk factors. One exception,
however, is the relationship between smoking and AMD.
As of 1999, at least seven studies consistently found that
smoking is strongly associated with AMD. This is one
more important reason for people to avoid and/or quit
smoking, especially if they have a family history of
AMD. Further research is needed to clarify the significance of the factors listed above so people may be
informed about lifestyle changes that may help decrease
their risk for AMD.
Demographics
Among adults aged 55 and older, AMD is the leading cause of vision loss in developed countries. The
chance to develop AMD increases with age, and although
it usually affects adults during their sixth and seventh
decades of life, it has been seen in some people in their
forties. It is estimated that among people living in developed countries, approximately one in 2,000 are affected
by AMD. By age 75, approximately 30% of people have
early or mild forms of AMD, and roughly 7% have an
advanced form of AMD. Since the number of people in
the United States aged 65 years or older will likely dou693
Macular degeneration—age-related
The ABCR gene maps to chromosome 1p22, and
people who have Stargardt macular dystrophy have mutations in each of their two alleles (gene copies). However,
the researchers who found mutations in the ABCR gene
among people with AMD located only one allele with a
mutation, which likely created an increased susceptibility
to AMD. They concluded that people with an ABCR
gene mutation in one allele could have an increased
chance to develop AMD during their lifetime if they also
had inherited other susceptibility genes, and/or had contact with environmental risk factors. Other scientists tried
to repeat this type of genetic research among people with
AMD in 1999, and were not able to confirm that the
ABCR gene is a strong genetic risk factor for this condition. However, it is possible that the differing research
results may have been caused by different research methods, and further studies will be necessary to understand
the importance of ABCR gene mutations in the development of susceptibility to AMD.
Macular degeneration—age-related
upon whether a person has dry or wet AMD. In addition,
the degree of vision loss and physical symptoms that can
be seen by an eye exam change over time. For example,
people with dry AMD usually develop vision loss very
slowly over a period of many years. Their vision may
change very little from one year to the next, and they usually do not lose central vision completely. However, individuals with wet AMD usually have symptoms that
worsen more quickly and they have a greater risk to
develop severe central vision loss, sometimes in as little
as a two-month period. Since people diagnosed with dry
AMD may go on to develop wet AMD, it is important for
them to take note of any changes in their symptoms and
to report them to their eye care specialist.
A retinal photograph showing macular degeneration.
(Custom Medical Stock Photo, Inc.)
ble between 1999 and 2024, the number of people
affected also should increase. Although AMD occurs in
both sexes, it is slightly more common in women.
The number of people affected with AMD is different in various parts of the world and it varies between different ethnic groups. Some studies suggest that AMD is
more common in Caucasians than in African Americans;
however, other reports suggest the numbers of people
affected in these two groups are similar. Some studies of
AMD among Japanese and other Asian ethnic groups
have shown an increasing number of affected individuals.
Further studies are needed to examine how often AMD
occurs in other ethnic groups as well.
Signs and symptoms
During eye examinations, eye care specialists may
notice physical changes in the retina and macula that
make them suspect the diagnosis of AMD. However,
affected individuals may notice:
• Decreased visual acuity (ability to see details) of both
up-close and distant objects
• Blurred central vision
• Decreased color vision
• Distorted view of lines and shapes
• A blind spot in the visual field
The majority of people with AMD maintain their
peripheral vision. The severity of symptoms depends
694
The physical symptoms of AMD eventually impact
people emotionally. One study published in 1998
reported that people with advanced stages of AMD feel
they have a significantly decreased quality of life. In
addition, they may have a limited ability to perform basic
daily activities due to poor vision, and as a result, they
often suffer psychological distress. Hopefully, improved
treatment and management will eventually change this
trend for affected individuals in the future.
Diagnosis
Eye care specialists use a variety of tests and examination techniques to determine if a person has AMD.
Some of these include:
• Acuity testing—Involves testing vision by determining
a person’s ability to read letters or symbols of various
sizes on an “eye chart” from a precise distance away
with specific lighting present.
• Color testing—Assesses the ability of the cone cells to
recognize colors by using special pictures made up of
dots of colors that are arranged in specific patterns.
• Amsler grid testing—Involves the use of a grid printed
on a piece of paper that helps determine the health of
the macula, by allowing people to notice whether they
have decreased central vision, distorted vision, or blind
spots.
• Fluorescein angiography—Involves the use of a fluorescent dye, injected into the bloodstream, in order to
look closely at the blood supply and blood vessels near
the macula. The dye allows the eye specialist to examine and photograph the retina and macula to check for
signs of wet AMD (i.e. abnormal blood vessel formation or blood leakage).
As of 2001, there are no genetic tests readily available to help diagnose AMD. Genetic research in the coming years will hopefully help scientists determine the
genetic basis of AMD. This could help diagnose people
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
• Magnifying lenses
• Telescopes
• Specialized prisms
• Large print books
• Reading machines
Treatment and management
• Computer programs that talk or enlarge printed information
Treatment
People with AMD may also find it useful to meet
with low-vision specialists who can help them adapt to
new lifestyle changes that may assist with daily living.
Eye care specialists can help people locate low-vision
specialists. There are also a number of nationwide and
international support groups available that provide education and support for individuals and families affected
by AMD.
There is no universal treatment available to cure
either wet or dry forms of AMD. However, some people
with wet AMD can benefit from laser photocoagulation
therapy. This treatment involves the use of light rays from
a laser to destroy the abnormal blood vessels that form
beneath the retina and macula and prevent further leakage of blood and fluid. Previously lost vision cannot be
restored with this treatment, and the laser can unfortunately damage healthy tissue as well, causing further loss
of vision.
In April 2000, the FDA approved the use of a lightactivated drug called Visudyne to help treat people with
wet AMD. Visudyne is a medication that is injected into
the bloodstream, and it specifically attaches to the abnormal blood vessels present under the macula in people
with AMD. When light rays from a laser land on the
blood vessels, the Visudyne is activated and can destroy
the abnormal vessels, while causing very little damage to
nearby healthy tissues. Although long term studies are
needed to determine the safety and usefulness of this
medication beyond two years, early reports find it an
effective way to reduce further vision loss.
Researchers have been trying to identify useful treatments for dry AMD as well. Laser photocoagulation
treatments are not effective for dry AMD since people
with this form do not have abnormal blood or fluid leakage. Although many drugs have been tested, most have
not improved visual acuity. However, one study published in October 2000, reported that people with dry
AMD who received a medication called Iloprost over a
six-month period noted improvements in visual acuity,
daily living activities and overall quality of life. Followup studies will be needed to determine how safe and useful this medication will be over time.
Management
Although no treatments can cure AMD, a number of
special devices can help people make the most of their
remaining vision. Some of these include:
• Walking canes
• Guide dogs
• Audiotapes
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Prognosis
People can live many years with AMD, although the
physical symptoms and emotional side effects often
change over time. The vision problems caused by dry
AMD typically worsen slowly over a period of years, and
people often retain the ability to read. However, for people who develop wet AMD, the chance to suddenly
develop severe loss of central vision is much greater.
Regular monitoring of vision by people with AMD (using
an Amsler grid) and by their eye care specialists, may
allow for early treatment of leaky blood vessels, therefore
reducing the chance for severe vision loss. As physical
symptoms worsen, people are more likely to suffer emotionally due to decreasing quality of life and independence. However, many low-vision devices and various
support groups can often provide much needed assistance
to help maintain and/or improve quality of life.
Resources
BOOKS
D’Amato, Robert, and Joan Snyder. Macular Degeneration:
The Latest Scientific Discoveries and Treatments for
Preserving Your Sight. New York: Walker & Co., 2000.
Solomon, Yale, and Jonathan D. Solomon. Overcoming
Macular Degeneration: A Guide to Seeing Beyond the
Clouds. New York: Morrow/Avon, 2000.
PERIODICALS
Bressler, Neil M., and James P. Gills. “Age related macular
degeneration.” British Medical Journal 321, no. 7274
(December 2000): 1425–1427.
Fong, Donald S. “Age-Related Macular Degeneration: Update
for Primary Care.” American Family Physician 61, no. 10
(May 2000): 3035–3042.
“Macular degeneration.” Harvard Women’s Health Watch 6, no.
2 (October 1998): 2–3.
695
Macular degeneration—age-related
with increased susceptibility before they have symptoms,
so they may benefit from early diagnosis, management
and/or treatment. This knowledge may also allow people
who are at a genetically increased risk for AMD to avoid
environmental risk factors and thus preserve or prolong
healthy vision.
Major histocompatibility complex
“Researchers set sights on vision disease.” Harvard Health
Letter 23, no.10 (August 1998):4–5.
“Self-test for macular degeneration.” Consumer Reports on
Health 12, no.12 (December 2000): 2.
ORGANIZATIONS
AMD Alliance International. PO Box 550385, Atlanta, GA
30355. (877) 263-7171. ⬍http://www.amdalliance.org⬎.
American Macular Degeneration Foundation. PO Box 515,
Northampton, MA 01061-0515. (413) 268-7660.
⬍http://www.macular.org⬎.
Foundation Fighting Blindness Executive Plaza 1, Suite 800,
11350 McCormick Rd., Hunt Valley, MD 21031. (888)
394-3937. ⬍http://www.blindness.org⬎.
Macular Degeneration Foundation. PO Box 9752, San Jose, CA
95157. (888) 633-3937. ⬍http://www.eyesight.org⬎.
Retina International. Ausstellungsstrasse 36, Zürich, CH-8005.
Switzerland (⫹41 1 444 10 77). ⬍http://www.retinainternational.org⬎.
Pamela J. Nutting, MS, CGC
Madelung deformity see Leri-Weill
dyschondrosteosis
Maffuci disease see Chondrosarcoma
I Major histocompatibility
complex
Definition
In humans, the proteins coded by the genes of the
major histocompatibility complex (MHC) include human
leukocyte antigens (HLA), as well as other proteins.
HLA proteins are present on the surface of most of the
body’s cells and are important in helping the immune
system distinguish ‘self’ from ‘non-self’.
Description
The function and importance of MHC is best understood in the context of a basic understanding of the function of the immune system. The immune system is
responsible for distinguishing ‘self’ from ‘non-self’, primarily with the goal of eliminating foreign organisms
and other invaders that can result in disease. There are
several levels of defense characterized by the various
stages and types of immune response.
Natural immunity
When a foreign organism enters the body, it is
encountered by the components of the body’s natural
696
immunity. Natural immunity is the non-specific first-line
of defense carried out by phagocytes, natural killer cells,
and components of the complement system. Phagocytes
are specialized white blood cells capable of engulfing
and killing an organism. Natural killer cells are also specialized white blood cells that respond to cancer cells
and certain viral infections. The complement system is a
group of proteins called the class III MHC that attack
antigens. Antigens consist of any molecule capable of
triggering an immune response. Although this list is not
exhaustive, antigens can be derived from toxins, protein,
carbohydrates, DNA, or other molecules from viruses,
bacteria, cellular parasites, or cancer cells.
Acquired immunity
The natural immune response will hold an infection
at bay as the next line of defense mobilizes through
acquired, or specific immunity. This specialized type of
immunity is usually needed to eliminate an infection and
is dependent on the role of the proteins of the major histocompatibility complex. There are two types of acquired
immunity. Humoral immunity is important in fighting
infections outside the body’s cells, such as those caused
by bacteria and certain viruses. Other types of viruses
and parasites that invade the cells are better fought by
cellular immunity. The major players in acquired immunity are the antigen-presenting cells (APCs), B-cells,
their secreted antibodies, and the T-cells. Their functions
are described in detail below.
Humoral immunity
In humoral immunity, antigen-presenting cells,
including some B-cells, engulf and break down foreign
organisms. Antigens from these foreign organisms are
then brought to the outside surface of the antigen-presenting cells and presented in conjunction with class II
MHC proteins. The helper T-cells recognize the antigen
presented in this way and release cytokines, proteins that
signal B-cells to take further action. B-cells are specialized white blood cells that mature in the bone marrow.
Through the process of maturation, each B-cell develops
the ability to recognize and respond to a specific antigen.
Helper T-cells aid in stimulating the few B-cells that can
recognize a particular foreign antigen. B-cells that are
stimulated in this way develop into plasma cells, which
secrete antibodies specific to the recognized antigen.
Antibodies are proteins that are present in the circulation,
as well as being bound to the surface of B-cells. They can
destroy the foreign organism from which the antigen
came. Destruction occurs either directly, or by ‘tagging’
the organism, which will then be more easily recognized
and targeted by phagocytes and complement proteins.
Some of the stimulated B-cells go on to become memory
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Cellular immunity
Another type of acquired immunity involves killer Tcells and is termed celluar immunity. T-cells go through
a process of maturation in the organ called the thymus, in
which T-cells that recognize ‘self’ antigens are eliminated. Each remaining T-cell has the ability to recognize
a single, specific, ‘non-self’ antigen that the body may
encounter. Although the names are similar, killer T-cells
are unlike the non-specific natural killer cells in that they
are specific in their action. Some viruses and parasites
quickly invade the body’s cells, where they are ‘hidden’
from antibodies. Small pieces of proteins from these
invading viruses or parasites are presented on the surface
of infected cells in conjunction with class I MHC proteins, which are present on the surface of most all of the
body’s cells. Killer T-cells can recognize antigen bound
to class I MHC in this way, and they are prompted to
release chemicals that act directly to kill the infected cell.
There is also a role for helper T-cells and antigen-presenting cells in cellular immunity. Helper T-cells release
cytokines, as in the humoral response, and the cytokines
stimulate killer T-cells to multiply. Antigen-presenting
cells carry foreign antigen to places in the body where
additional killer T-cells can be alerted and recruited.
The major histocompatibility complex clearly performs an important role in functioning of the immune
system. Related to this role in disease immunity, MHC is
important in organ and tissue transplantation, as well as
playing a role in susceptibility to certain diseases. HLA
typing can also provide important information in parentage, forensic, and anthropologic studies. These various
roles and the practical applications of HLA typing are
discussed in greater detail below.
Genetic profile
Present on chromosome 6, the major histocompatibility complex consists of more than 70 genes, classified
into class I, II, and III MHC. There are multiple alleles,
or forms, of each HLA gene. These alleles are expressed
as proteins on the surface of various cells in a co-dominant manner. This diversity is important in maintaining
an effective system of specific immunity. Altogether, the
MHC genes span a region that is four million base pairs
in length. Although this is a large region, 99% of the time
these closely-linked genes are transmitted to the next
generation as a unit of MHC alleles on each chromosome
6. This unit is called a haplotype.
Class I
Class I MHC genes include HLA-A, HLA-B, and
HLA-C. Class I MHC are expressed on the surface of
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
almost all cells. They are important for displaying antigen
from viruses or parasites to killer T-cells in cellular immunity. Class I MHC is also particularly important in organ
and tissue rejection following transplantation. In addition
to the portion of class I MHC coded by the genes on chromosome 6, each class I MHC protein also contains a small,
non-variable protein component called beta-2 microglobulin coded by a gene on chromosome 15. Class I HLA
genes are highly polymorphic, meaning there are multiple
forms, or alleles, of each gene. There are at least 57 HLAA alleles, 111 HLA-B alleles, and 34 HLA-C alleles.
Class II
Class II MHC genes include HLA-DP, HLA-DQ,
and HLA-DR. Class II MHC are particularly important in
humoral immunity. They present foreign antigen to
helper T-cells, which stimulate B-cells to elicit an antibody response. Class II MHC is only present on antigen
presenting cells, including phagocytes and B-cells. Like
class I MHC, there are hundreds of alleles that make up
the class II HLA gene pool.
Class III
Class III MHC genes include the complement system (i.e. C2, C4a, C4b, Bf). Complement proteins help to
activate and maintain the inflammatory process of an
immune response.
Demographics
There is significant variability of the frequencies of
HLA alleles among ethnic groups. This is reflected in
anthropologic studies attempting to use HLA-types to
determine patterns of migration and evolutionary relationships of peoples of various ethnicity. Ethnic variation
is also reflected in studies of HLA-associated diseases.
Generally speaking, populations that have been subject to
significant patterns of migration and assimilation with
other populations tend to have a more diverse HLA gene
pool. For example, it is unlikely that two unrelated individuals of African ancestry would have matched HLA
types. Conversely, populations that have been isolated
due to geography, cultural practices, and other historical
influences may display a less diverse pool of HLA types,
making it more likely for two unrelated individuals to be
HLA-matched.
Testing
Organ and tissue transplantation
There is a role for HLA typing of individuals in various settings. Most commonly, HLA typing is used to
establish if an organ or tissue donor is appropriately
matched to the recipient for key HLA types, so as not to
697
Major histocompatibility complex
cells, which are able to mount an even faster response if
the antigen is encountered a second time.
Disease susceptibility
There is an established relationship between the
inheritance of certain HLA types and susceptibility to
specific diseases. Most commonly, these are diseases that
are thought to be autoimmune in nature. Autoimmune
diseases are those characterized by inflammatory reactions that occur as a result of the immune system mistakenly attacking ‘self’ tissues. The basis of the HLA
association is not well understood, although there are
some hypotheses. Most autoimmune diseases are characterized by the expression of class II MHC on cells of the
body that do not normally express these proteins. This
may confuse the killer T-cells, which respond inappropriately by attacking these cells. Molecular mimicry is
another hypothesis. Certain HLA types may ‘look like’
antigen from foreign organisms. If an individual is
infected by such a foreign virus or bacteria, the immune
system mounts a response against the invader. However,
there may be a ‘cross-reaction’ with cells displaying the
HLA type that is mistaken for foreign antigen. Whatever
the underlying mechanism, certain HLA-types are known
factors that increase the relative risk for developing specific autoimmune diseases. For example, individuals who
carry the HLA B-27 allele have a relative risk of 77–90
for developing ankylosing spondylitis—meaning such an
individual has a 77- to 90-fold chance of developing this
form of spinal and pelvic arthritis, as compared to someone in the general population. Selected associations are
listed below, together with the approximate corresponding relative risk of disease.
In addition to autoimmune disease, HLA-type less
commonly plays a role in susceptibility to other diseases,
including cancer, certain infectious diseases, and metabolic diseases. Conversely, some HLA-types confer a
protective advantage for certain types of infectious disease. In addition, there are rare immune deficiency diseases that result from inherited mutations of the genes of
components of the major histocompatibility complex.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
TABLE 1
HLA disease associations
Disease
MHC allele
Approximate relative risk
Ankylosing spondylitis
Celiac disease
Diabetes, Type 1
Diabetes, Type 1
Diabetes, Type 1
Graves disease
Hemochromatosis
Lupus
Multiple sclerosis
Myasthenia gravis
Psoriasis vulgaris
Rheumatoid arthritis
B27
DR3 + DR7
DR3
DR4
DR3 + DR4
DR3
A3
DR3
DR2
B8
Cw6
DR4
77–90
5–10
5
5–7
20–40
5
6–20
1–3
2–4
2.5–4
8
3–6
The relative risks indicated in this table refer to the increased chance of a
patient with an MHC allele to develop a disorder as compared to an
individual without one. For example, a patient with DR4 is three to six
times more likely to have rheumatoid arthritis and five to seven times
more likely to develop type 1 diabetes than an individual without the DR4
allele.
Parentage
Among other tests, HLA typing can sometimes be
used to determine parentage, most commonly paternity, of a child. This type of testing is not generally
done for medical reasons, but rather for social or legal
reasons.
Forensics
HLA-typing can provide valuable DNA-based evidence contributing to the determination of identity in
criminal cases. This technology has been used in domestic criminal trials. Additionally, it is a technology that has
been applied internationally in the human-rights arena.
For example, HLA-typing had an application in
Argentina following a military dictatorship that ended in
1983. The period under the dictatorship was marked by
the murder and disappearance of thousands who were
known or suspected of opposing the regime’s practices.
Children of the disappeared were often ‘adopted’ by military officials and others. HLA-typing was one tool used
to determine non-parentage and return children to their
biological families.
Anthropologic studies
HLA-typing has proved to be an invaluable tool in
the study of the evolutionary origins of human populations. This information, in turn, contributes to an under699
Major histocompatibility complex
elicit a rejection reaction in which the recipient’s immune
system attacks the donor tissue. In the special case of
bone marrow transplantation, the risk is for graft-versushost disease (GVHD), as opposed to tissue rejection.
Because the bone marrow contains the cells of the
immune system, the recipient effectively receives the
donor’s immune system. If the donor immune system
recognizes the recipient’s tissues as foreign, it may begin
to attack, causing the inflammation and other complications of GVHD. As advances occur in transplantation
medicine, HLA typing for transplantation occurs with
increasing frequency and in various settings.
Malignant hyperthermia
standing of cultural and linguistic relationships and practices among and within various ethnic groups.
Resources
BOOKS
Abbas, A.K., et al. Cellular and Molecular Immunology.
Philadelphia: W.B. Saunders, 1991.
Doherty, D.G., and G.T. Nepom. “The human major histocompatibility complex and disease susceptibility.” In Emery
and Rimoin’s Principles and Practice of Medical
Genetics. 3rd ed. Ed. D.L. Rimoin, J.M. Connor, and R.E.
Pyeritz, 479–504. New York: Churchill Livingston, 1997.
Jorde L.B., et al. “Immunogenetics.” In Medical Genetics. 2nd
ed. St. Louis: Moseby, 1999.
PERIODICALS
Diamond, J.M. “Abducted orphans identified by grandpaternity
testing.” Nature 327 (1987): 552–53.
Svejgaard, A., et al. “Associations between HLA and disease
with notes on additional associations between a ‘new’
immunogenetic marker and rheumatoid arthritis.” HLA
and Disease—The Molecular Basis. Alfred Benzon
Symposium. 40 (1997): 301–13.
Trachtenberg, E.A., and H.A. Erlich. “DNA-based HLA typing
for cord blood stem cell transplantation.” Journal of
Hematotherapy 5 (1996): 295–300.
WEBSITES
“Biology of the immune system.” The Merck Manual
⬍http://www.merck.com/pubs/mmanual_home/sec16/176
.htm⬎.
Jennifer Denise Bojanowski, MS, CGC
Male turner syndrome see Noonan
syndrome
Malignant fever see Malignant
hyperthermia
Malignant hyperpyrexia see Malignant
hyperthermia
perature (i.e. hyperthermia). Although MH can usually be
treated successfully, it sometimes leads to long-term
physical illness or death. Research has identified a number of genetic regions that may be linked to an increased
MH susceptibility.
Description
Unusual response to anesthesia was first reported in
a medical journal during the early 1960s, when physicians described a young man in need of urgent surgery for
a serious injury. He was very nervous about exposure to
anesthesia, since he had 10 close relatives who died during or just after surgeries that required anesthesia. The
patient himself became very ill and developed a high temperature after he was given anesthesia. During the next
decade, more cases of similar reactions to anesthesia
were reported, and specialists began using the term
malignant hyperthermia to describe the newly recognized
condition. The word hyperthermia was used because people with this condition often rapidly develop a very high
body temperature. The word malignant referred to the
fact that the majority (70–80%) of affected individuals
died. The high death rate in the 1960s occurred because
the underlying cause of the condition was not understood,
nor was there any known treatment (other than basically
trying to cool the person’s body with ice).
Increased awareness of malignant hyperthermia and
scientific research during the following decades
improved medical professionals’ knowledge about what
causes the condition, how it affects people, and how it
should be treated. MH can be thought of as a chain reaction that is triggered when a person with MH susceptibility is exposed to specific drugs commonly used for
anesthesia and muscle relaxation.
Triggering drugs that may lead to malignant hyperthermia include:
• halothane
• enflurane
• isoflurane
I Malignant hyperthermia
• sevoflurane
Definition
• methoxyflurane
Malignant hyperthermia (MH) is a condition that
causes a number of physical changes to occur among
genetically susceptible individuals when they are
exposed to a particular muscle relaxant or certain types of
medications used for anesthesia. The changes may
include increased rate of breathing, increased heart rate,
muscle stiffness, and significantly increased body tem700
• desflurane
• ether
• succinylcholine
Once an MH susceptible person is exposed to one or
more of these anesthesia drugs, they can present with a
variety of signs. One of the first clues that a person is susceptible to MH is often seen when they are given a musGALE ENCYCLOPEDIA OF GENETIC DISORDERS
The series of events that occur after exposure to trigger drugs is activated by an abnormally high amount of
calcium inside muscle cells. This is due to changes in the
chemical reactions that control muscle contraction and
the production of energy. Calcium is normally stored in
an area called the sarcoplasmic reticulum, which is a system of tiny tubes located inside muscle cells. This system
of tubes allows muscles to contract (by releasing calcium) and to relax (by storing calcium) in muscle cells.
Calcium also plays an important role in the production of
energy inside cells (i.e. metabolism). There are at least
three important proteins located in (or nearby) the sarcoplasmic reticulum that control how much calcium is
released into muscle cells and thus help muscles contract.
One of these proteins is a “calcium release channel” protein that has been named the ryanodine receptor protein,
or RYR. This protein (as well as the gene that tells the
body how to make it) has been an important area of
research. For some reason, when people with MH susceptibility are exposed to a trigger drug, they can develop
very high levels of calcium in their muscle cells. The trigger drugs presumably stimulate the proteins that control
the release of calcium, causing them to create very high
levels of calcium in muscle cells. This abnormally high
calcium level then leads to increased metabolism, muscle
stiffness, and the other symptoms of MH.
The amount of time that passes between the exposure to trigger drugs and the appearance of the first symptoms of MH varies between different people. Symptoms
begin within 10 minutes for some individuals, although
several hours may pass before symptoms appear in others. This means that some people do not show signs of
MH until they have left the operating room and are recovering from surgery. In addition, some individuals who
inherit MH susceptibility may be exposed to trigger
drugs numerous times during multiple surgeries without
any complications. However, they still have an increased
risk to develop an MH episode during future exposures.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
KEY TERMS
Anesthesia—Lack of normal sensation (especially
to pain) brought on by medications just prior to
surgery or other medical procedures.
Genetic heterogeneity—The occurrence of the
same or similar disease, caused by different genes
among different families.
Hyperthermia—Body temperature that is much
higher than normal (i.e. higher than 98.6°F).
Masseter spasm—Stiffening of the jaw muscles.
Often one of the first symptoms of malignant
hyperthermia susceptibility that occurs after exposure to a trigger drug.
Metabolism—The total combination of all of the
chemical processes that occur within cells and tissues of a living body.
Sarcoplasmic reticulum—A system of tiny tubes
located inside muscle cells that allow muscles to
contract and relax by alternatively releasing and
storing calcium.
Trigger drugs—Specific drugs used for muscle
relaxation and anesthesia that can trigger an
episode of malignant hyperthermia in a susceptible person. The trigger drugs include halothane,
enflurane, isoflurane, sevoflurane, desflurane,
methoxyflurane, ether, and succinylcholine.
This means that people who have an increased risk for
MH susceptibility due to their family history cannot presume they are not at risk simply because they previously
had successful surgeries. Although MH was frequently a
fatal condition in the past, a drug called dantrolene
sodium became available in 1979, which greatly
decreased the rate of both death and disability.
Genetic profile
Susceptibility to MH is generally considered to be
inherited as an autosomal dominant trait. “Autosomal”
means that males and females are equally likely to be
affected. “Dominant” refers to a specific type of inheritance in which only one copy of a person’s gene pair
needs to be changed in order for the susceptibility to be
present. In this situation, an individual susceptible to MH
receives a changed copy of the same gene from one parent (who is also susceptible to MH). This means that a
person with MH susceptibility has one copy of the
changed gene and one copy of the gene that works well.
The chance that a parent with MH susceptibility will
701
Malignant hyperthermia
cle relaxant called succinyl choline. This drug generally
causes some stiffness in the masseter (jaw) muscles in
most people. However, individuals with MH susceptibility can develop a much more severe form of jaw stiffness
called masseter spasm when they receive this drug. They
may develop muscle stiffness in other parts of their bodies as well. When exposed to any of the trigger drugs
listed above (inhalants for anesthesia), people with MH
susceptibility can develop an increased rate of metabolism in the cells of their body, resulting in rapid breathing, rapid heartbeat, high body temperature (over 110°F),
muscle stiffness, and muscle breakdown. If these signs
are not recognized, treated, or able to be controlled, brain
damage or death can occur due to internal bleeding, heart
failure, or failure other organs.
Malignant hyperthermia
have a child who is also susceptible is 50% for each pregnancy. The same parent would also have a 50% chance to
have a non-susceptible child with each pregnancy.
It is not unusual for people to not know they inherited a genetic change that causes MH susceptibility. This
is because they typically do not show symptoms unless
they are exposed to a specific muscle relaxant or certain
anesthetics, which may not be needed by every person
during his or her lifetime. In addition, people who inherit
MH susceptibility do not always develop a reaction to
trigger drugs, which means