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

an underlying muscle problem or a nerve problem. Nerves stimulate muscles to contract. A non-functioning muscle due to a nerve problem often causes the same symptoms as a non-functioning muscle caused by a problem with the muscle.

Genetic testing

Genetic testing is a useful diagnostic tool because the diagnosis can be made without an invasive muscle biopsy. Blood from the person suspected to have muscular dystrophy is analyzed at a specialty laboratory. Genetic testing will confirm that the DMD gene is abnormal in most males affected with muscular dystrophy (70% with DMD and 85% with BMD). The disease causing mutation will be unidentifiable in some males who have muscular dystrophy. Therefore, an abnormal test result is definitive, but a normal test result is not. In these cases, muscle biopsy may be necessary to confirm the diagnosis. Muscle biopsy may be helpful to determine whether a young person with mild symptoms has Duchenne or Becker even when the diagnosis of muscular dystrophy is established by genetic testing.

The severity of the mutation is correlated to the severity of the disease. For example, mutations that completely eliminate the dystrophin protein are associated with DMD much more often than they are associated with BMD. Particular mutations have been associated with intellectual impairment. The severity of symptoms can be somewhat predicted by the mutation present.

Even when a mutation in the DMD gene has been identified in the affected family member, genetic testing to determine whether or not the females are carriers may not be straightforward.

In some families, a special form of genetic testing called “linkage testing” may be helpful. Linkage genetic testing can be performed when the diagnosis of Duchenne or Becker muscular dystrophy is certain in more than one family member but no mutation is identified in the DMD gene. Linkage testing requires the participation of multiple family members. Unique DNA sequences within the gene and flanking the gene are analyzed to determine whether the sequences are those associated with the deleterious gene or with the normal gene. This method is not 100% accurate.

If a woman knows that she is a carrier, prenatal and preimplantation diagnosis are available. If the specific DMD or BMD mutation has been identified in a family member, genetic testing can be performed on the fetus. The procedures used to obtain fetal cells are chorionic villus sampling (CVS) and amniocentesis. CVS is usually performed between 10 and 12 weeks of pregnancy, and amniocentesis is usually performed after 16 weeks.

Whether amniocentesis or CVS is performed, chromosomal analysis of the fetal cells will show whether the baby is male or female. Linkage testing may also be performed prenatally.

Treatment and management

There is no cure for muscular dystrophy. However, doctors are getting better at treating the symptoms. Many researchers are searching for preventative measures and for a cure. In 2001, therapies focus on treating the associated symptoms.

Preventative measures

Exercise and physical therapy help to prevent joint contractures and maintain mobility. Avoiding obesity is important. Orthopedic devices may delay the age at which an affected boy begins to use a wheelchair, and are often used to treat scoliosis. Motorized wheelchairs and other devices help an affected person who has become disabled to maintain his independence as long as possible. When the cardiac muscles become affected, respiratory care may be necessary. Cardiac function should be evaluated in adult males with Becker muscular dystrophy even when skeletal muscles are mildly affected. Some women who are carriers of Duchenne muscular dystrophy develop heart disease related to changes in their cardiac muscle. Therefore, surveillance for heart disease should be a consideration for women who are carriers of DMD.

Experimental therapies

Some researchers are trying to deliver normal dystrophin protein to the muscle. If this were done by gene therapy, a normal copy of the DMD gene would be inserted into the muscle cells. In 2001, neither gene therapy nor dystrophin protein replacement is available. In fact, this research is in the early stages. But the theoretical possibility gives researchers hope that in the future there may be a cure.

Researchers have also experimentally transferred healthy muscle cells into the tissue of individuals with muscular dystrophy. This is not a standard treatment as of 2001. However, it provides another hope that in the future an effective treatment will be developed.

Claims have been made that a class of medications called corticosteroids slows the progression of muscle destruction in muscular dystrophy. The use of these drugs is controversial. Corticosteroids have not been proven to have a long-term effect. Also, corticosteroids have many serious side effects. Cortisone is a corticosteroid, and prednisone is similar to cortisone.

dystrophy muscular Duchenne

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Discovering the DMD gene allowed researchers to create animal models for muscular dystrophy. They have created mice and other animals that have Duchenne muscular dystrophy in order to more effectively study the disease and test the efficacy of treatments. This development also provides hope for the future.

Prognosis

The prognosis of Duchenne muscular dystrophy is confinement to a wheelchair by the age of 12 years, and usually death by the late teens or early twenties. The prognosis for Becker muscular dystrophy varies. Some individuals with BMD require a wheelchair after 16 years of age, but others remain ambulatory into middle adulthood. Some mildly affected individuals never require a wheelchair. The average life expectancy for Becker muscular dystrophy is the mid-forties. Both conditions are progressively debilitating.

Because Duchenne is a relatively common and severe condition, many people very actively promote further funding, research, and support of affected individuals. Associations to help families with muscular dystrophy have chapters all over the world. Families and researchers are hopeful that the genetic discoveries of the 1990s will lead to new treatments and cures in the next millennium. However, the obstacles between understanding the pathogenesis of a disease and creating an effective treatment are large. This is especially true of muscular dystrophy.

Resources

BOOKS

Bayley, Susan C. Our Man Sam: Making the Most Out of Life with Muscular Dystrophy. 1998.

Bergman, Thomas. Precious Time: Children Living with

Muscular Dystrophy. Stevens, Gareth Inc., 1996.

Burnett, Gail Lemley. Muscular Dystrophy, Heatlh Watch

Series. Enslow Publishers, Inc., 2000.

Emery, Alan. Muscular Dystrophy, Oxford Medical Publications.

2nd ed. New York: Oxford University Press, Inc., 2000. Lockshin, Michael. Guarded Prognosis: A Doctor and His

Patients Talk About Chronic Disease and How to Cope with It. New York: Hill and Wang, 1998.

Siegal, Irwin M. Muscular Dystrophy in Children: A Guide for

Families. Demos Medical Publishing, Inc., 1999.

PERIODICALS

Leahy, Michael. “A Powerful Swimmer, Boy with Muscular Dystrophy Relishes Competition.” The Washington Post (29 July 1999).

ORGANIZATIONS

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. [phone] or [phone].http://www.mdausa.org .

Muscular Dystrophy Campaign. 7-11 Prescott Place, London, SW4 6BS. UK 44(0) 7720 8055. info@muscular-dystro- phy.org. http://www.muscular-dystrophy.org .

Muscular Dystrophy Family Foundation. 615 North Alabama St., Ste. 330, Indianapolis, IN 46204-1213. (317) 6328255 or [phone]. [e-mail]. http://www

.mdff.org .

Parent Project for Muscular Dystrophy Research. 1012 N. University Blvd., Middletown, OH 45042. [phone] or [phone]. [e-mail]. http://www

.parentdmd.org .

WEBSITES

Addresses of Muscular Dystrophy and Neuromuscular Disorder Associations around the world. http://www.w-a-n-d-a

.org/mda_addresses.htm .

National Center for Biotechnology Information. “Duchenne Muscular Dystrophy.” http://www.ncbi.nlm.nih.gov/ disease/DMD.html .

National Institute of Neurological Disorders and Stroke. “NINDS Muscular Dystrophy Information Page.”http://nindsiis2.ninds.nih.gov/health_and_medical/ disorders/md.htm .

Iowa Health Book: Orthopaedics. “Treating Scoliosis in Muscular Dystrophy.” http://www.vh.org/Patients/IHB/ Ortho/Peds/Scoliosis/MD/ScoliosisMD.html .

Leiden University Medical Center, Netherlands. “Information for Non-scientists on Muscular Dystrophies.” http://dmd

.nl/nonsciuk.html .

OTHER

A Teacher’s Guide to Duchenne Muscular Dystrophy. Booklet. Muscular Dystrophy Association. http://www.mdausa

.org/publications/tchrdmd/index.html .

Facts About Duchenne and Becker Muscular Dystrophies

(DMD and BMD). Booklet. Muscular Dystrophy Association. http://www.mdausa.org/publications/fa-dmdbmd

.html .

Muscular Dystrophy. Videotape. Dartmouth-Hitchcock Medical Center. http://www.dartmouth.edu/~drisin/videos/md

.shtml .

Michelle Q. Bosworth, MS, CGC

Dwarfism see Pituitary dwarfism syndrome

I Dysplasia

Definition

Dysplasia is a combination of two Greek words; dys-, which means difficult or disordered; and plassein, to form. In other words, dysplasia is the abnormal or disordered organization of cells into tissues. All abnormalities relating to abnormal tissue formation are classified as dysplasias.

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Description

Tissues displaying abnormal cellular organization are called dysplastic. Dysplasias may occur as the result of any number of stimuli. Additionally dysplasia may occur as a localized or a generalized abnormality. In a localized dysplasia, the tissue abnormality is confined to the tissue in a single area, or body part. In a generalized dysplasia, the abnormal tissue is an original defect leading to structural consequences in different body parts.

Localized dysplasia

Localized dysplasia may occur as the result of any number of stimuli and affect virtually any organ. Stimuli leading to localized dysplasia may include viruses, chemicals, mechanical irritation, fire, or even sunlight. Sunburned skin, for example, is dysplastic. The dysplasia caused from sunburn, however, corrects itself as the sunburned skin heals.

Any source of irritation causing inflammation of an area will result in temporary dysplasia. Generally, when the source of irritation is removed the dysplasia will correct itself. Removing the irritant generally allows cell structure and organization to return to normal in a localized dysplasia.

Unfortunately, dysplasia can become permanent. This can occur when a source of irritation to a given area cannot be found and removed, or for completely unknown reasons. A continually worsening area of dysplasia can develop into an area of malignancy (cancer). Tendencies toward dysplasia can be genetic. They may also result from exposure to irritants or toxins, such as cigarette smoke, viruses, or chemicals.

CERVICAL DYSPLASIA The Pap smear, a medical procedure commonly performed on women, is a test for dysplasia of a woman’s cervix. The cervix is the opening to a woman’s uterus that extends into the vagina. It is a common area where cancers may develop. A Pap smear involves sampling the outer cells of a woman’s cervix to look for microscopic cellular changes indicative of dysplasia, or abnormal tissue changes. Less than five percent of Pap smears indicate cervical dysplasia. Cervical dysplasia is most common in women who are 25 to 35 years old.

The degree of dysplasia present in cervical cells can be used as an indicator for progression to a cancerous condition. Early treatment of cervical dysplasia is very effective in halting progression of the dysplasia to cancer. Essentially, all sexual risk factors correlate with dysplasia. Exposure to the AIDS virus (HIV) or certain strains of human papilloma virus (HPV) raises a woman’s risk to develop cervical dysplasia. Increased risk is also linked to having unprotected sex at an early age, having unpro-

Dysplasia is characterized by abnormal cell organization in body tissues. The tissue sample above shows a variety of cell shapes and arrangements typical of this disorder.

(Photo Researchers, Inc.)

tected sex with many partners, or becoming pregnant before age 20. Smoking increases a woman’s risk to develop cervical dysplasia. Prenatal exposure to diethylstilbestrol (DES), a hormonal drug prescribed from 1940 to 1971 to reduce miscarriages, also increases a woman’s risk for cervical dysplasia. Exactly how these risk factors are connected to cervical dysplasia is not well understood.

The American Cancer Society recommends that all women begin yearly Pap tests at age 18, or when they become sexually active, whichever occurs earlier. If a woman has had three negative annual Pap tests in a row, this test may be done less often at the judgment of a woman’s health care provider.

Generalized dysplasia

A generalized dysplasia often presents as multiple malformations in a variety of structures. Any structural consequences are due to the particular tissue organization defect and the spectrum of organs that utilize the dysplastic tissue. Generalized dysplasias are often genetic. They may be inherited or occur due to a new genetic change in an individual. The structural problems associated with generalized dysplasias usually begin during embryonic development.

This type of dysplasia is classified according to the specific tissue affected. Generalized dysplasias account

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K E Y T E R M S

Acondroplasia—An autosomal dominant form of dwarfism caused by a defect in the formation of cartilage at the ends of long bones. Affected individuals typically have short limbs, a large head with a prominent forehead and flattened profile, and a nor- mal-sized trunk.

Amastia—A birth defect involving absent breast(s).

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Cartilage—Supportive connective tissue which cushions bone at the joints or which connects muscle to bone.

Chondrocyte—A specialized type of cell that secretes the material which surrounds the cells in cartilage.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases.

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46

chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

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

Clubfoot—Abnormal permanent bending of the ankle and foot. Also called talipes equinovarus.

Collagen—The main supportive protein of cartilage, connective tissue, tendon, skin, and bone.

Corpus callosum—A thick bundle of nerve fibers deep in the center of the forebrain that provides communications between the right and left cerebral hemispheres.

de novo mutation—Genetic mutations that are seen for the first time in the affected person, not inherited from the parents.

Deoxyribonucleic acid (DNA)—The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

DNA mutation analysis—A direct approach to the detection of a specific genetic mutation or mutations using one or more laboratory techniques.

Dysplasia—The abnormal growth or development of a tissue or organ.

Ectoderm—The outermost of the three embryonic cell layers, which later gives rise to the skin, hair, teeth, and nails.

Ectrodactyly—A birth defect involving a split or cleft appearance of the hands and/or feet, also referred to as a “lobster-claw malformation.”

Epiphyses—the growth area at the end of a bone.

(continued)

for some important groups of inherited disorders including the skeletal dysplasias and ectodermal dysplasias.

SKELETAL DYSPLASIAS Skeletal dysplasias affect the growth, organization, and development of the bony skeleton. These conditions are always genetic. The effects of skeletal dysplasias vary. A mild skeletal dysplasia may cause someone to be of shortened height without any other complication. Other skeletal dysplasias may severely reduce height, causing dwarfism with dispropor-

tion and other bone deformity. The most severe skeletal dysplasias are incompatible with life, causing babies to die before or soon after birth.

The skeletal dysplasias include achondroplasia, hypochondroplasia, thanatophoric dysplasia, achondrogenesis, diastrophic dysplasia, atelosteogenesis, spondyloepiphyseal dysplasia, Kniest dysplasia, Stickler syndrome, pseudoachondoplasia, metaphyseal dysplasia, and several others.

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KEY TERMS ( C O N T I N U E D )

Fetus—The term used to describe a developing human infant from approximately the third month of pregnancy until delivery. The term embryo is used prior to the third month.

Fibroblast—Cells that form connective tissue fibers like skin.

Founder effect—Increased frequency of a gene mutation in a population that was founded by a small ancestral group of people, at least one of whom was a carrier of the gene mutation.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Genitals—The internal and external reproductive organs in males and females.

Gonads—The organ that will become either a testis (male reproductive organ) or ovary (female reproductive organ) during fetal development.

Hallucal polydactyly—The appearance of an extra great toe.

Hormone—A chemical messenger produced by the body that is involved in regulating specific bodily functions such as growth, development, and reproduction.

Hypertelorism—A wider-than-normal space between the eyes.

Hyperthermia—Body temperature that is much higher than normal (i.e. higher than 98.6°F).

Hypochondroplasia—An autosomal dominant form of dwarfism whose physical features are similar to those of achondroplasia but milder. Affected individuals have mild short stature and a normal facial appearance.

Linkage analysis—A method of finding mutations based on their proximity to previously identified genetic landmarks.

Metacarpal—A hand bone extending from the wrist to a finger or thumb.

Metaphyses—The growth zone of the long bones located between the epiphyses the ends (epiphyses) and the shaft (diaphysis) of the bone.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Nanism—Short stature.

Ovary—The female reproductive organ that produces the reproductive cell (ovum) and female hormones.

Philtrum—The center part of the face between the nose and lips that is usually depressed.

Sulfate—A chemical compound containing sulfur and oxygen.

Testes—The male reproductive organs that produce male reproductive cells (sperm) and male hormones.

Tetralogy of Fallot—A congenital heart defect consisting of four (tetralogy) associated abnormalities: ventricular septal defect (VSD—hole in the wall separating the right and left ventricles); pulmonic stenosis (obstructed blood flow to the lungs); the aorta “overrides” the ventricular septal defect; and thickening (hypertrophy) of the right ventricle.

Tissue—Group of similar cells that work together to perform a particular function. The four basic types of tissue include muscle, nerve, epithelial, and connective tissues.

Vertebra—One of the 23 bones which comprise the spine. Vertebrae is the plural form.

Achondroplasia is a common, highly recognizable skeletal dysplasia. This disorder occurs in approximately one in 20,000 live births. Achondroplasia affects bone growth resulting in short stature, a large head, characteristic facial features, and disproportionately short arms and legs. This disorder is caused by a mutation in a single gene called fibroblast growth factor receptor three (FGFR3). Achondroplasia may be inherited like most generalized dysplasias, but more commonly it occurs due

to a new mutation in a family. Over 80% of cases of achondroplasia are sporadic, or due to new mutations. The appearance of new mutations for achondroplasia is more frequently observed in children born to older fathers.

Hypochondroplasia is a common, milder skeletal dysplasia caused by different mutations in the gene responsible for achondroplasia, the FGFR3 gene. People with hypochondroplasia display varying degrees of short

Dysplasia

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Infants with thanatophoric dysplasia have abnormal pelvic and leg bone formation. The affected infant shown on top has the characteristic “telephone receiver” shape. An infant with normal bone formation is shown on the bottom for comparison. (Greenwood Genetic Center)

stature and disproportion of limbs. People with mild symptoms may never be diagnosed. The body of a person with hypochondroplasia appears short and broad with a long torso and short limbs. Lifespan is normal. Like achondroplasia, hypochondroplasia is inherited in an autosomal dominant manner.

ECTODERMAL DYSPLASIAS Ectodermal dysplasias affect the growth and development of tissues derived from the early outer layer of embryonic tissue known as the ectoderm. Tissues derived from the ectoderm include hair, fingernails, skin, sweat glands, and teeth. People with ectodermal dysplasias display abnormalities in at

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least two derivatives of the ectoderm. Ectodermal dysplasia (ED) can take many different forms because so many tissues are derived from the ectoderm. Over 150 types of ectodermal dysplasias have been identified.

The effects of ectodermal dysplasias range from mild to severe. They are divided into two major groups based on the presence or absence or normal sweating. Sweat production is normal in hidrotic (sweating) types and reduced in hypohidrotic (decreased sweating) types. Types with reduced or absent sweating are generally more severe.

Christ-Siemens-Touraine syndrome (CST), a hypohidrotic (decreased sweating) ectodermal dysplasia, is a common, well-understood type of ectodermal dysplasia. People with this type of ectodermal dysplasia are not able to sweat or form tears normally. They are very sensitive to light and are not able to control their body temperature well due to their reduced sweating. Intelligence is normal. People with CST often have small or missing teeth, eyebrows, and eyelashes. Head hair is usually sparse, but fingernails are normal. CST is usually X- linked recessive, affecting only males with full symptoms of the disease. In some cases, female carriers show mild symptoms of the disease. Rarer autosomal dominant and autosomal recessive forms can affect males and females.

Clouston ectodermal dysplasia, a hidriotic (sweating) ectodermal dysplasia, also known as ectodermal dysplasia 2 (ED2) is found more commonly in people of French Canadian descent. People with this form of ED have partial to total baldness with normal teeth, severely abnormal fingernails, and darkly pigmented areas of skin, especially over joints. They have underdeveloped eyebrows and eyelashes and may be born with teeth. They may also have thickened skin on the soles of their feet and the palms of their hands. Features including mental retardation and strabismus, or crossed eyes, may occur with this disorder, however intelligence is usually normal. This form of ED is inherited in an autosomal dominant manner. Any affected person has a 50% chance to pass the disorder to each of their children.

Resources

BOOKS

Moore, Keith L. The Developing Human: Clinically Oriented

Embryology. Philadelphia: W.B. Saunders Company, 1998.

PERIODICALS

Wright, Michael J. “Hypochondroplasia.” Gene Map Locus (2001): 16.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329. [phone]. http://www.cancer.org .

Children’s Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. [phone] or [phone]. [e-mail]. http://www.ccakids.com .

FACES: The National Craniofacial Assocation. PO Box 11082, Chattanooga, TN 37401. [phone] or (800) 3322373. [e-mail]. http://www.faces-cranio

.org/ .

Greenberg Center for Skeletal Dysplasias. 600 North Wolfe St., Blalock 1012C, Baltimore, MD 21287-4922. [phone] http://www.med.jhu.edu/Greenberg.Center/ Greenbrg.htm .

Johns Hopkins University-McKusick Nathans Institute of Genetic Medicine 600 North Wolfe St., Blalock 1008, Baltimore, MD 21287-4922. [phone].

Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. [phone] or (888) LPA2001. [e-mail]. http://www.lpaonline

.org .

National Foundation for Ectodermal Dysplasias. PO Box 114, 410 E Main, Mascoutah, IL 62258-0114. [phone]. Fax: [phone]. http://www.nfed.org .

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

.rarediseases.org .

Judy C. Hawkins, MS

Dysplasia giantism syndrome X-linked (DGSX) see Simpson-Golabi-Behmel syndrome

I Dystonia

Definition

Dystonia is a group of complex neurological movement disorders. While the disorders vary in their symptoms, causes, progression, and treatment, dystonia is characterized by involuntary muscle contractions and spasms that result in abnormal postures and movements. Focal dystonias—which affect a single part of the body, such as the face, arms, or vocal chords—are the most common.

Description

Dystonia is not a single disease, but a group of disorders with a variety of symptoms. The most common characteristic of dystonia is twisting, repetitive, and sometimes painful movements that affect a specific part of the body, such as the arms, legs, trunk, neck, eyelids,

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K E Y T E R M S

Basal ganglia—A section of the brain responsible for smooth muscular movement.

Blepharospasm—A focal dystonia marked by excessive blinking and involuntary closing of the eyes.

Cervical dystonia—A focal dystonia that causes neck muscles to contract involuntarily–leading to abnormal movements and posture of the head and neck. Also known as spasmodic torticollis.

Early on-set dystonia—Dystonia that begins in adolescence. Most common among Jewish persons of Eastern European ancestry.

Limb dystonia—Involuntary cramp or spasm that affects the hands. Also known as writer’s cramp.

Primary dystonia—Dystonia that has no connection to disease or injury. Often hereditary.

Secondary dystonia—Dystonia that occurs due to disease, injury, or another non-hereditary factor. Also known as symptomatic dystonia.

Spasmodic dysphonia—A focal dystonia that causes involuntary “spasms” of the vocal cords— leading to interruptions of speech and a decrease in voice quality.

face, or vocal cords. Cervical dystonia, which affects the head and neck, is the most common adult form of dystonia, followed by blepharospasm (eyelids), spasmodic dysphonia (larynx), and limb dystonias (hands).

Researchers believe that dystonia is caused by a malfunction in the basal ganglia, the part of the brain involved in regulating voluntary and involuntary movement. A Berlin neurologist, Hermann Oppenheim, first coined the term “dystonia” in 1911 after observing muscle spasm and variation in muscle tone in several of his young patients. The term was widely accepted and used by neurologists; however, the definition has changed over time.

Today dystonia is classified in several ways, based on cause, location, and age at onset.

Dystonia can be caused by many different factors. It may occur due to trauma, stroke, certain infections and diseases (e.g. Wilson disease, multiple sclerosis), reactions to certain neuroleptic or antipsychotic drugs (e.g. haloperidol or chlorpromazine), birth injury, or heavymetal or carbon monoxide poisoning. This type of dystonia is called secondary or symptomatic dystonia. About

half of dystonia cases have no connection to disease or injury and are referred to as primary dystonia. Many of these cases appear to be inherited.

The most useful classification for physicians is location, or distribution of the dystonia. Focal dystonia involves a single body part while multifocal dystonia affects multiple body parts. In generalized dystonia, symptoms begin in an arm or a leg and advance, eventually affecting the rest of the body.

The patient’s age at the onset of symptoms helps physicians identify the cause and determine the probability of disease progression. Dystonia that begins in childhood is often hereditary, begins in the leg or (less commonly) the arm, and may progress to other parts of the body. Dystonia that begins in adolescence (early onset dystonia) may be hereditary, often begins in the arm or neck, and is more likely to progress than the childhood form. Adult-onset dystonia typically begins as focal or multifocal and is sporadic in origin.

Genetic profile

The majority of primary dystonia cases are believed to be hereditary and occur as the result of a faulty gene. Most cases of early-onset primary dystonia are due to a mutation in the DYT-1 gene, which was first identified as a factor in the disorder in 1987.

Dystonia appears when an individual has one copy of the mutated gene and one copy of the normal gene; however, only 30–40% of individuals with the mutated genes develop symptoms.

Demographics

Dystonia affects more than 300,000 people in North America, affecting all races and ethnic groups. Early onset idiopathic torsion dystonia has a higher frequency among Ashkenazi Jews—Jews of Eastern European ancestry.

Dystonia is the third most common movement disorder, after Parkinson disease and tremor.

Signs and symptoms

Early symptoms of dystonia may include a deterioration in handwriting, foot cramps, tremor, voice or speech difficulties, and a tendency of one foot to pull up or drag while walking. Initially, the symptoms may be very mild and only noticeable after prolonged exertion, stress, or fatigue. Over a period of time, the symptoms may become more noticeable and widespread.

Symptoms may first occur in childhood (between the ages of 5 and 17 years) or early adulthood. In general, the

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earlier the onset of symptoms, the greater the chance that the disease will progress with advancing age.

Diagnosis

There is no specific diagnostic test for dystonia and the diagnosis is often based on clinical signs and symptoms. Diagnosis may be difficult because the signs are similar to those of other disorders; the involuntary muscle contractions are often incorrectly attributed to stress, stiff neck, dry eyes, tics, or psychogenic or neurological disorders. According to Mount Sinai Medical Center, 90% of dystonia patients are initially misdiagnosed.

One thing that is helpful in differentiating dystonic movements from those caused by other disorders is the timing of the movements. Dystonic movements tend to increase during activity, nervousness, and emotional stress; and usually disappear during sleep.

Treatment and management

There is no cure for dystonia. However, symptoms such as spasms and pain can usually be managed with a combination of treatments.

No one treatment has proven universally effective. A physician’s approach to treatment is typically threetiered, encompassing oral medications, injections of therapeutic agents (e.g. botulinum toxin) directly into dystonic muscle, and surgery. Surgery, which involves cutting nerves and muscles or placing a lesion in the basal ganglia to reduce movement, is usually reserved for the most severe cases. Alternative medicine, such as physical therapy, speech therapy, and biofeedback, may also have a role in treatment management.

The cause and location of a patient’s dystonia will play a factor in the treatment methods chosen by the physician. In secondary dystonia, treating the underlying cause may prove effective in improving or eliminating the associated symptoms. Patients with focal dystonia often respond best to targeted methods—such as injections of botulinum toxin or surgery—while patients with dystonia may first need to be treated with oral medications to alleviate the multiple symptoms.

Prognosis

Dystonia is not fatal; however, it is a chronic disorder and prognosis can be difficult to predict.

Resources

PERIODICALS

Adler, Charles H. “Strategies for Controlling Dystonia; Overview of Therapies That May Alleviate Symptoms.” Postgraduate Medicine (October 2000). http://www

.postgradmed.com/issues/2000/10_00/adler.htm . Ozelius, Laurie J, Jeffrey W. Hewett, Curtis E. Page, Susan B.

Bressman, Patricia L. Kramer, Christo Shalish, Deborah de Leon, Mitchell F. Brin, Deborah Raymond, David P. Corey, Stanley Fahn, Neil J. Risch, Alan J. Buckler, James F. Gusella, and Xandra O. Breakefield. “The Early-Onset Torsion Dystonia Gene (DYT1) Encodes an ATP-Binding Protein.” Nature Genetics 17 (September 1997): 40.

ORGANIZATIONS

Bachmann-Strauss Dystonia & Parkinson Foundation, Inc. Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1490, New York, NY 10029. [phone].http://www.dystonia-parkinsons.org .

Dystonia Medical Research Foundation. One East Wacker Dr., Suite 2430, Chicago, IL 60601. [phone].http://www.dystonia-foundation.org .

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

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

.rarediseases.org .

WE MOVE (Worldwide Education and Awareness for Movement Disorders). Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1490, New York, NY 10029. [phone]. http://www.wemove.org .

WEBSITES

“Gene Sequenced for Disabling Childhood Movement Disorder: Early-Onset Torsion Dystonia Protein Found.”

National Institute of Neurological Disorders and Stroke.

September 3, 1997. www.ninds.nih.gov/news_and_ events/pressrelease _ disabling _ childhhod _ move - ment_090397.htm .

“Early Onset Primary Dystonia.” GeneClinics. March 30, 1999.www.geneclinics.org/profiles/dystonia .

Michelle L. Brandt

Dystrophia myotonica 2 see Myotonic dystrophy

Dystonia

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E

I Ectodermal dysplasia

Definition

The ectodermal dysplasias are a group of hereditary conditions characterized by abnormal hair, teeth, fingernails and toenails, and sweat glands.

Description

All ectodermal dysplasias have a genetic etiology and involve abnormal development and growth of ectodermally derived tissues. The ectoderm is the outermost layer of the developing embryo, which gives rise to the hair, teeth, nails, and skin. More than 100 different ectodermal dysplasia conditions have been described in the medical literature. The most common of these is hypohidrotic ectodermal dysplasia, which may account for up to 80% of all ectodermal dysplasias.

Other ectodermal dysplasia conditions include ectro- dactyly-ectodermal dysplasia-clefting (EEC) syndrome, hidrotic ectodermal dysplasia (Clouston syndrome), Hay-Wells syndrome, incontintentia pigmenti, RappHodgkin syndrome, tricho-dento-osseous syndrome, and tooth-nail (Witkop) syndrome. Each of these conditions appears to account for 1–4% of all ectodermal dysplasias.

Most ectodermal dysplasia conditions are associated with sparse hair that has abnormal texture. The hair may appear thin, dry, and brittle. In some cases, premature balding may occur.

The teeth of those with ectodermal dysplasia are typically abnormal and reduced in number. A characteristic conical and sharply pointed tooth shape is often present. In some cases, the majority of teeth are missing.

In some ectodermal dysplasia conditions, the fingernails and toenails may be absent or abnormally formed. The nails may be thickened, thinned, brittle, or display unusual ridging or pitting.

The skin may be thin, show abnormal pigmentation, and be prone to eczema (a condition of dry skin charac-

terized by inflammation and itching). The nasal and respiratory passages may be dry, leading to abnormal discharges and increased infections. In hypohydrotic ectodermal dysplasia, the sweat glands are reduced in number, which may lead to dangerous hyperthermia (high body temperature).

Other abnormalities that may occur in the ectodermal dysplasia conditions include amastia (absent mammary glands), cleft lip and/or palate, ectrodactyly (split hand or split foot), and abnormal bands of skin in the mouth or connecting the eyelids.

Many individuals with ectodermal dysplasia have normal cognitive function. A minority of cases may involve some degree of mental retardation. In the case of hypohydrotic ectodermal dysplasia, untreated hyperthermic episodes can lead to brain damage and cognitive impairment.

Genetic profile

Hypohydrotic ectodermal dysplasia is inherited in an X-linked recessive manner. Sixty to 75% of carrier females may show variable manifestations of the condition. The responsible gene has been named EDA; it has been mapped to the Xq12-q13.1 chromosomal region but has not yet been identified.

Incontinentia pigmenti is caused by chromosomal rearrangements disrupting the Xp11 region (type I incontintentia pigmenti) or by a gene mapping to Xq28 (type II or familial incontintentia pigmenti). Both forms appear to be lethal in males, as nearly all affected patients (97–98%) are female.

Most other ectodermal dysplasias are transmitted in an autosomal dominant fashion. Rarely, autosomal recessive transmission may occur.

The molecular genetics of the ectodermal dysplasia conditions are poorly understood. Investigation has been hampered by the great variability displayed by many of these conditions, similar features shown by different ectodermal dysplasias, and genetic heterogeneity (differ-

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