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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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Tourette syndrome

Prognosis

Although there is no cure, the prognosis for people with TGN is quite good. Despite the fact that the majority of people with this disorder will require medical treatment to control bleeding, patients rarely die of massive blood loss. Interestingly, the severity of bleeding appears to decrease with increasing age. Barring any catastrophic accident which results in uncontrollable bleeding, lifespan is approximately the same as the general population.

Resources

BOOKS

Cotran R. S. Robbins Pathologic Basis of Disease.

Philadelphia: W.B. Saunders, 1999.

“Disorders of the Platelet and Vessel Wall.” In Harrison’s

Principles of Internal Medicine, edited by A.S. Fauci. New York: McGraw-Hill, 1998.

“Disorders of the Platelets and the Blood Vessels.” In Nelson Textbook of Pediatrics, edited by R.E. Behrman. Philadelphia: W.B. Saunders, 2000, pp 1520-1525.

“Hereditary Disorders of Platelet Function.” In Wintrobe’s Clinical Hematology, edited by R. Lee. Philadelphia: Lippincott Williams & Wilkins, 1999, pp 16621669.

PERIODICALS

French, D.L., and U. Seligsohn. “Platelet Glycoprotein IIb/IIIa Receptors and Glanzmann’s Thrombasthenia.” Arteriosclerosis Thrombosis and Vascular Biology 20 (March 2000): 607610.

Tomiyama, Y. “Glanzmann Thrombasthenia: Integrin Alpha IIb Beta 3 Deficiency”. International Journal of Hematology

72 (December 2000): 448-454.

ORGANIZATIONS

Glanzmann’s Thrombasthenia Support Group. 28 Duke Rd.,

Newton, Hyde, SK14 4JB. UK 0161-368-0219

WEBSITES

“Glanzmann Thrombasthenia.” Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/entrez/dispomim

.cgi?id=187800 .

Oren Traub, MD, PhD

Thrombocytopenia absence of radius syndrome see TAR syndrome

I Tourette syndrome

Definition

Tourette syndrome (TS) is an inherited disorder of the nervous system, characterized by a variable expression of unwanted movements and noises (tics).

Description

The first references in the literature to what might today be classified as Tourette syndrome largely describe individuals who were wrongly believed to be possessed by the devil. In 1885 Gilles de la Tourette, a French neurologist, provided the first formal description of this syndrome, which he described as an inherited neurological condition characterized by motor and vocal tics.

Although vocal and motor tics are the hallmark of Tourette syndrome, other symptoms such as the expression of socially inappropriate comments or behaviors, obsessive compulsive disorder, attention deficit disorder, self injuring behavior, depression, and anxiety also appear to be associated with Tourette syndrome. Most research suggests that Tourette syndrome is an autosomal dominant disorder, although a gene responsible for Tourette syndrome has not yet been discovered.

Genetic profile

The cause of Tourette syndrome is unknown although some studies suggest that the tics in Tourette syndrome are caused by an increased amount of a neurotransmitter called dopamine. A neurotransmitter is a chemical found in the brain that helps to transmit information from one brain cell to another. Other studies suggest that the defect in Tourette syndrome involves another neurotransmitter called serotonin or involves other chemicals required for normal functioning of the brain.

Most studies suggest that Tourette syndrome is an autosomal dominant disorder with decreased penetrance, although this has not been proven and may not be true in all families. An autosomal dominant disorder results from a change in one copy of a pair of genes. Individuals with an autosomal dominant disorder have a 50% chance of passing on the changed gene to their children. Decreased penetrance means that not all people who inherit the changed gene will develop symptoms. There is some evidence that females who inherit the Tourette syndrome gene have a 70% chance of exhibiting symptoms and males have a 99% chance of having symptoms. It has been suggested that other gene and environmental factors may play a role in the development of symptoms in people who inherit the changed gene but none have been discovered. Some researchers believe that Tourette syndrome has different causes in different individuals or is caused by changes in more than one gene, although these theories are less substantiated. Further research is needed to establish the cause of Tourette syndrome.

Demographics

Tourette syndrome is found in all populations and all ethnic groups but is three to four times more common in

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males than females and is more common in children than adults. The exact frequency of Tourette syndrome is unknown but estimates range from 0.05% to 3%.

Signs and symptoms

Motor and vocal tics

The principal symptoms of Tourette syndrome include simple and complex motor and vocal tics. Simple motor tics are characterized by brief muscle contractions of one or more limited muscle groups. An eye twitch is an example of a simple motor tic. Complex motor tics tend to appear more complicated and purposeful than simple tics and involve coordinated contractions of several muscle groups. Some examples of complex motor tics include the act of hitting oneself and jumping. Copropraxia, the involuntary display of unacceptable/ obscene gestures, and echopraxia, the imitation of the movement of another individual, are other examples of complex motor tics.

Vocal tics are actually manifestations of motor tics that involve the muscles required for vocalization. Simple vocal tics include stuttering, stammering, abnormal emphasis of part of a word or phrase, and inarticulate noises such as throat clearing, grunts, and high-pitched sounds. Complex vocal tics typically involve the involuntary expression of words. Perhaps the most striking example of this is coprolalia, the involuntary expression of obscene words or phrases, which occurs in fewer than one-third of people with Tourette syndrome. The involuntary echoing of the last word, phrase, sentence or sound vocalized by oneself (phalilalia) or of another person or sound in the environment (echolalia) are also classified as complex tics.

The type, frequency, and severity of tics exhibited varies tremendously between individuals with Tourette syndrome. Tourette syndrome has a variable age of onset and tics can start anytime between infancy and age 18. Initial symptoms usually occur before the early teens and the mean age of onset for both males and females is approximately seven years of age. Most individuals with symptoms initially experience simple muscle tics involving the eyes and the head. These symptoms can progress to tics involving the upper torso, neck, arms, hands, and occasionally the legs and feet. Complex motor tics are usually the latest onset muscle tics. Vocal tics usually have a later onset then motor tics. In some rare cases, people with Tourette syndrome suddenly present with multiple, severe, or bizarre symptoms.

Not only is there extreme variability in clinical symptoms between individuals with Tourette syndrome, but individuals commonly experience a variability in

K E Y T E R M S

Attention deficit disorder (ADD)—Disorder characterized by a short attention span, impulsivity, and in some cases hyperactivity.

Autosomal dominant—A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.

Coprolalia—The involuntary expression of obscene words or phrases.

Copropraxia—The involuntary display of unacceptable/obscene gestures.

Decreased penetrance—Individuals who inherit a changed disease gene but do not develop symptoms.

Dysphoria—Feelings of anxiety, restlessness, and dissatisfaction.

Echolalia—Involuntary echoing of the last word, phrase, or sentence spoken by someone else or sound in the environment.

Echopraxia—The imitation of the movement of another individual.

Neurotransmitter—Chemical in the brain that transmits information from one nerve cell to another.

Obsessive compulsive disorder (OCD)—Disorder characterized by persistent, intrusive, and senseless thoughts (obsessions) or compulsions to perform repetitive behaviors that interfere with normal functioning.

Phalilalia—Involuntary echoing of the last word, phrase, sentence, or sound vocalized by oneself.

Tic—Brief and intermittent involuntary movement or sound.

type, frequency, and severity of symptoms within the course of their lifetime. Adolescents with Tourette syndrome often experience unpredictable and variable symptoms, which may be related to fluctuating hormone levels and decreased compliance in taking medications. Adults often experience a decrease in symptoms or a complete end to symptoms.

A number of factors appear to affect the severity and frequency of tics. Stress appears to increase the frequency and severity of tics while concentration on another part of the body that is not taking part in a tic can result in the temporary alleviation of symptoms.

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Tourette syndrome

Relaxation, following attempts to suppress the occurrence of tics, may result in an increased frequency of tics. An increased frequency and severity of tics can also result from exposure to drugs such as steroids, cocaine, amphetamines, and caffeine. Hormonal changes such as those that occur prior to the menstrual cycle can also increase the severity of symptoms.

Other associated symptoms

People with Tourette syndrome are more likely to exhibit non-obscene, socially inappropriate behaviors such as expressing insulting or socially unacceptable comments or socially unacceptable actions. It is not known whether these symptoms stem from a more general dysfunction of impulse control that might be part of Tourette syndrome.

Tourette syndrome appears to also be associated with attention deficit disorder (ADD). ADD is a disorder characterized by a short attention span and impulsivity and in some cases hyperactivity. Researchers have found that 21–90% of individuals with Tourette syndrome also exhibit symptoms of ADD, whereas 2–15% of the general population exhibit symptoms of ADD.

People with Tourette syndrome are also at higher risk for having symptoms of obsessive compulsive disorder (OCD). OCD is a disorder characterized by persistent, intrusive, and senseless thoughts (obsessions) or compulsions to perform repetitive behaviors that interfere with normal functioning. A person with OCD, for example, may be obsessed with germs and may counteract this obsession with continual hand washing. Symptoms of OCD are present in 1.9–3% of the general population, whereas 28–50% of people with Tourette syndrome have symptoms of OCD.

Self-injurious behavior (SIB) is also seen more frequently in those with Tourette syndrome. Approximately 34–53% of individuals with Tourette syndrome exhibit some form of self-injuring behavior. The SIB is often related to OCD but can also occur in those with Tourette syndrome who do not have OCD.

Symptoms of anxiety and depression are also found more commonly in people with Tourette syndrome. It is not clear, however, whether these symptoms are symptoms of Tourette syndrome or occur as a result of having to deal with the symptoms of moderate to severe Tourette syndrome.

People with Tourette syndrome may also be at increased risk for having learning disabilities and personality disorders and may be more predisposed to behaviors such as aggression, antisocial behaviors, severe temper outbursts, and inappropriate sexual behavior. Further controlled studies need to be performed, however, to

ascertain whether these behaviors are symptoms of Tourette syndrome.

Diagnosis

Tourette syndrome cannot be diagnosed through a blood test. The diagnosis is made through observation and interview of the patient and discussions with other family members. The diagnosis of Tourette syndrome is complicated by a variety of factors. The extreme range of symptoms of this disorder makes it difficult to differentiate Tourette syndrome from other disorders with similar symptoms. Diagnosis is further complicated by the fact that some tics appear to be within the range of normal behavior. For example, an individual who only exhibits tics such as throat clearing and sniffing may be misdiagnosed with a medical problem such as allergies. In addition, bizarre and complex tics such as coprolalia may be mistaken for psychotic or “bad” behavior. Diagnosis is also confounded by individuals who attempt to control tics in public and in front of health care professionals and deny the existence of symptoms. Although there is disagreement over what criteria should be used to diagnosis Tourette syndrome, one aid in the diagnosis is the

Diagnostical and Statistical Manual of Mental Disorders

(DSM-IV). The DSM-IV outlines suggested diagnostic criteria for a variety of conditions including Tourette syndrome such as:

Presence of both motor and vocal tics at some time during the course of the illness.

The occurrence of multiple tics nearly every day through a period of more than one year, without a remission of tics for a period of greater than three consecutive months.

The symptoms cause distress or impairment in functioning.

Age of onset of prior to 18 years of age.

The symptoms are not due to medications or drugs and are not related to another medical condition.

Some physicians critique the DSM-IV criteria, citing that they do not include the full range of behaviors and symptoms seen in Tourette syndrome. Others criticize the criteria since they limit the diagnosis to those who experience a significant impairment, which may not be true for individuals with milder symptoms. For this reason many physicians use their clinical judgment as well as the DSMIV criteria as a guide to diagnosing Tourette syndrome.

Treatment and management

There is no cure for Tourette syndrome, and treatment involves the control of symptoms through educa-

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tional and psychological interventions and/or medications. The treatment and management of Tourette syndrome varies from patient to patient and should focus on the alleviation of the symptoms that are most bothersome to the patient or that cause the most interference with daily functioning.

Psychological and educational interventions

Psychological treatments such as counseling are not generally useful for the treatment of tics but can be beneficial in the treatment of associated symptoms such as obsessive-compulsive behavior and attention deficit disorder. Counseling may also help individuals to cope better with the symptoms of this disorder and to have more positive social interactions. Psychological interventions may also help people cope better with stressors that can normally be triggers for tics and negative behaviors. Relaxation therapies may, however, increase the occurrence of tics. The education of family members, teachers, and peers about Tourette syndrome can be helpful and may help to foster acceptance and prevent social isolation.

Medications

Many people with mild symptoms of Tourette syndrome never require medications. Those with severe symptoms may require medications for all or part of their lifetime. The most effective treatment of tics associated with Tourette syndrome involves the use of drugs such as Haloperidol, Pimozide, Sulpiride, and Tiapride, which decrease the amount of dopamine in the body. Unfortunately, the incidence of side effects, even at low dosages, is quite high. The short-term side effects can include sedation, dysphoria, weight gain, movement abnormalities, depression, and poor school performance. Long-term side effects can include phobias, memory difficulties, and personality changes. These drugs are therefore better candidates for short-term rather than long-term therapy.

Tourette syndrome can also be treated with other drugs such as clonidine, clonazepam, and risperidone, but the efficacy of these treatments is unknown. In many cases, treatment of associated conditions such as ADD and OCD is often more of a concern than the tics themselves. Clonidine used in conjunction with stimulants such as Ritalin may be useful for treating people with Tourette syndrome who also have symptoms of ADD. Stimulants should be used with caution in individuals with Tourette syndrome since they can sometimes increase the frequency and severity of tics. OCD symptoms in those with Tourette syndrome are often treated with drugs such as Prozac, Luvox, Paxil, and Zoloft.

In many cases the treatment of Tourette syndrome with medications can be discontinued after adolescence. Trials should be performed through the gradual tapering off of medications and should always be done under a doctor’s supervision.

Prognosis

The prognosis for Tourette syndrome in individuals without associated psychological conditions is often quite good, and only approximately 10% of Tourette syndrome individuals experience severe tic symptoms. Approximately 30% of people with Tourette syndrome will experience a decrease in the frequency and severity of tics and another 30–40% will experience a complete end of symptoms by late adolescence. The other 30–40% will continue to exhibit moderate to severe symptoms in adulthood. There does not appear to be a definite correlation between the type, frequency, and severity of symptoms and the eventual prognosis. Patients with severe tics may experience social difficulties and may isolate themselves from others in fear of shocking and embarrassing them. People with Tourette syndrome who have other symptoms such as obsessive compulsive disorder, attention deficit disorder, and self-injurious behavior usually have a poorer prognosis.

Resources

BOOKS

Haerle, Tracy, ed., and Jim Eisenreich. Children with Tourette

Syndrome: A Parent’s Guide. Bethesda, MD: Woodbine House, 1992.

Leckman, James, and Donald Cohen. Tourette’s Syndrome:

Tics, Obsessions, Compulsions: Development, Psychopathology and Clinical Care. New York: John Wiley & Sons, 1999.

PERIODICALS

Alsobrook, J.P. II, and D.L. Pauls. “The Genetics of Tourette Syndrome.” Neurologic Clinics 15 (May 1997): 381–393.

Chappell, P.B., L.D. Scahill, and J.F. Leckman. “Future Therapies of Tourette Syndrome.” Neurologic Clinics 15 (May 1997): 429–450.

Eidelberg, D., et al. “The Metabolic Anatomy of Tourette’s Syndrome.” Neurology 48 (April 1997): 927–934.

Freeman, R.D. “Attention Deficit Hyperactivity Disorder in the Presence of Tourette Syndrome.” Neurologic Clinics 15 (May 1997): 411–420.

Lichter, D.G., and L.A. Jackson. “Predictors of Clonidine Response in Tourette Syndrome: Implications and Inferences.” Journal of Child Neurology 11 (March 1997): 93–97.

Robertson, Mary. “Tourette Syndrome, Associated Conditions and the Complexities of Treatment.” Brain 123 (2000): 425–462.

syndrome Tourette

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Treacher Collins syndrome

ORGANIZATIONS

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424.http://www.ninds.nih.gov .

National Tourette Syndrome Association, Inc. 42-40 Bell Blvd., Bayside, NY 11361-2820. (718) 224-2999. Fax: (718) 279-9596. tourette@ix.netcom.com.

Tourette Syndrome Foundation of Canada. 194 Jarvis Street, #206, Toronto, ONT M5B 2B7. Canada (800) 361-3120. tsfc.org@sympatico.ca. http://www.tourette.ca .

OTHER

“About Tourette Syndrome.” Tourette Help. http://www

.tourettehelp.com/pages/patient/about.html .

“Tourette’s Disorder.” Internet Mental Health.

http://www.mentalhealth.com/fr20.html .

Lisa Maria Andres, MS, CGC

Translation see Chromosomal abnormalities

I Treacher Collins syndrome

Definition

Treacher Collins syndrome (TCS) is a genetic disorder involving abnormal facial development. Individuals with TCS have underdevelopment of the jawbone, cheekbones, ears, and eye area. These features range widely from mild to severe. Intelligence and lifespan are usually normal.

Description

TCS was first described by E. Treacher Collins in 1900 after observation of two individuals with similar facial abnormalities. In 1940, Franceschetti and Klein gave TCS another name, mandibulofacial dysostosis. TCS is also sometimes called Franceschetti-Klein syndrome or Franceschetti syndrome.

The features of TCS result from a problem in early embryonic development. After an embryo forms, there are cells that are unspecialized and have the ability to develop into any type of cell in any part of the body (neural crest cells). Early in development, the neural crest cells travel to different areas of the embryo and specialize to become a specific type of cell for a specific organ or body part. The branchial arches is the area where neural crest cells specialize to develop the bone structure and features of the face. In individuals with

TCS there is thought to be an error in the movement of the neural crest cells to the branchial arches or in the specialization of those cells once they reach the branchial arches. The result is underdevelopment of the facial bones, eyes, and ears.

Individuals with mild features of TCS may go undiagnosed. Sometimes adults do not know they have TCS until they have a child with more noticeable features. This can cause feelings of guilt for the parent. Children with more moderate to severe features of TCS look strikingly different and may be teased or shunned. These children are at risk for psychological stress and low self-esteem. Even adults with TCS who are productive and successful may battle issues of social stigma and low self-esteem regarding their facial differences.

Genetic profile

TCS is an autosomal dominant condition. Children of an affected parent have a 50% chance of inheriting the disorder. Males and females are affected equally. The severity of symptoms ranges widely, even among members of the same family. Therefore, the severity of a child’s features cannot be predicted by the features of the affected parent.

About 40% of babies born with TCS have one affected parent. The other 60% are assumed to have a new, sporadic gene mutation (alteration). If a child has a new mutation (one that is not carried by the parents) then his or her siblings will have an extremely low chance of also having TCS. When a baby with TCS is born to seemingly normal parents, it is important to examine both parents carefully for mild features of TCS in order to give them accurate recurrence risks.

The gene for TCS is on chromosome 5 and is called TCOF1. This gene produces a protein that has been named treacle. Disease-causing TCOF1 mutations result in absent or inactive treacle. The exact role of treacle is not known but it is thought to be involved in early embryo neural crest cell movement or specialization in the branchial arches.

Demographics

TCS is rare and affects an estimated one in 25,000 to 50,000 live births.

Signs and symptoms

TCS is described as a craniofacial condition because its features are all related to the head and face. The overall head size may be smaller than average (microcephaly). The outer corners of the eyes slant

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downward. There may be colobomas on the lower eyelids, giving the lids a droopy appearance. The bridge of the nose is usually wide. Most individuals with TCS have underdeveloped cheekbones (malar bones) which give that area of the face a flat or sunken appearance. The lower jaw and chin are usually small and retroverted (jawbone points downward toward the neck instead of pointing out perpendicular to the neck). Many individuals also have a large mouth. Cleft palate (with or without cleft lip) is seen in one-quarter to one-third of patients with TCS.

Ear abnormalities are also common in TCS. The ears may be low-set, small, misshapen, or absent. For this reason, hearing loss or deafness is a common feature of TCS. The hearing loss is usually due to abnormalities in the middle ear structures rather than the outer ear structures.

Infants with moderate or severe malar bone underdevelopment may have compressed airways. These babies can have problems breathing after birth and may need a respirator or tracheostomy. A small, retroverted jaw and chin can cause feeding problems that may warrant a feeding tube.

The severity of features present at birth remains constant throughout life. TCS does not get progressively better or worse as an individual ages.

Diagnosis

The diagnosis of TCS is usually made by physical examination and identification of the typical facial features. Computerized tomography (CT scans) can be used to determine the degree of underdevelopment of the facial bone structure.

There are other syndromes that have facial appearances that resemble TCS. A complete physical examination of other body systems can help to establish a diagnosis of TCS. TCS can be distinguished from Nager syndrome and Miller syndrome if no abnormalities are present in the hands or arms. TCS can be distinguished from oculoauriculovertebral (OAV) conditions (for example, Goldenhar syndrome) because facial involvement is bilateral (affecting both sides of the face) and the spinal column is normal.

If there are several people in a family with TCS, genetic linkage studies can be performed. Linkage studies require blood samples from many family members, both affected and unaffected. Markers on the TCOF1 gene are analyzed and compared to determine which gene version is shared by affected family members. The disease-causing gene should be present in all affected family members and absent from all unaffected mem-

K E Y T E R M S

Coloboma—An abnormality on the upper or lower eyelid that often gives the lid a droopy appearance.

Craniofacial—Relating to or involving both the head and the face.

Tracheostomy—An opening surgically created in the trachea (windpipe) through the neck to improve breathing.

bers. Linkage studies can be performed on an unborn baby to determine if the baby inherited the family’s dis- ease-causing gene. Prenatal ultrasound can also be used to look for facial features of TCS. While there have been reports of prenatal diagnosis of TCS with ultrasound only, babies with mild features may appear normal. Detection may also depend on the skill of the physician performing the ultrasound and his or her experience with features of TCS.

Treatment and management

Newborn infants with severe TCS may require a ventilator, tracheostomy, or feeding tube if life-threatening breathing or feeding problems exist. A cleft palate can be repaired with surgery. Hearing aids can help individuals with hearing loss.

For most individuals, the problems of TCS are largely cosmetic. Plastic surgery can help to build the bone structure of the face, which may improve appearance as well as breathing and feeding. Surgeons can use bone grafts to build up the underdeveloped cheekbones. The jawbone can be “lengthened” and its angle repositioned. The bridge of the nose can be narrowed. Ears can be reconstructed using cartilage from the ribcage. Surgery can also be performed on the eye area.

This reconstruction may take multiple surgeries at different ages. Each individual must be evaluated for his or her unique features and needs. Surgeries are timed with facial growth and emotional needs and maturity of the patient.

Prognosis

A small percentage of newborns with TCS will have life-threatening breathing difficulties, and infant deaths can occur. However, the majority of individuals with TCS have a normal lifespan.

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Triose phosphate isomerase deficiency

Resources

PERIODICALS

Dixon, M.J. “Treacher Collins Syndrome.” Journal of Medical Genetics 32 (1995): 806–08.

Posnick, J.C., and R.L. Ruiz. “Treacher Collins Syndrome: Current Evaluation, Treatment, and Future Directions.”

Cleft Palate-Craniofacial Journal 37, no. 5 (September 2000): 483+.

ORGANIZATIONS

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 3322373. faces@faces-cranio.org. http://www.faces-cranio

.org/ .

Treacher Collins Foundation. Box 683, Norwich, VT 05055. (800) 823-2055.

WEBSITE

“A Guide to Understanding Treacher Collins Syndrome.”

Children’s Craniofacial Association. http://www

.ccakids.com/srvSyndBklt.stm .

Amie Stanley, MS

I Triose phosphate isomerase deficiency

Definition

Triose phosphate isomerase (TPI) deficiency is a rare non-sex-linked (autosomal) disorder that is a result of an insufficient amount of the enzyme triose phosphate isomerase. This disorder is inherited as a dominant trait and it is known to be caused by more than one different mutation in the same gene (allelic variants).

Description

Triose phosphate isomerase is an enzyme involved in the breakdown of glucose into the energy required to sustain cellular metabolism. Glucose is first converted into the chemical pyruvate. Pyruvate then enters the tricarboxylic acid cycle (TCA cycle) to produce ATP, the chemical form of energy used by the cells. Glucose is broken down to the chemical pyruvate via a chemical pathway that involves 10 enzymes. TPI is the fifth enzyme in this reaction chain. The two major products of the reaction proceeding the TPI reaction are D-glycer- aldehyde-3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). These two chemicals are isomers, which means that they have the same chemical formulas but different chemical structures. TPI is the enzyme that converts DHAP into GAP. This conversion (isomeriza-

tion) is important because it is only GAP that is used in the subsequent steps in the reaction pathway to the essential pyruvate molecules.

Under normal physiological conditions, DHAP is produced in much greater quantities than GAP (approximately 20:1). Therefore, it is essential that TPI convert the DHAP to GAP to increase the overall efficiency of pyruvate production from glucose. Individuals affected with TPI deficiency have extremely low levels of TPI activity because the enzyme that they do produce is not properly formed and, thus, it is highly inefficient.

Genetic profile

The gene that is responsible for the production of TPI has been localized to a region on chromosome 12. There are at least five mutations in this gene that lead to TPI deficiency. In every case, very slight changes in the chemical structure of TPI occur such that the TPI produced is less effective than a normal TPI molecule, especially when the body is hot, either from the weather or from exercise.

Demographics

TPI deficiency is extremely rare. In 1998, there were only 13 people known to be living with TPI deficiency, eleven children and two adult Hungarian brothers affected with an extremely mild form of the disease. Since 1998, at least five of these children have passed away. The documented rarity of this disorder does not seem to coincide with the observed frequency of reduced TPI activity in the population.

In a 1996 study of unselected individuals of Caucasian and Japanese descent, a Japanese researcher found that approximately five out of every 1,000 individuals had TPI activity that was only half of the normal TPI activity. In a separate study, it was estimated that nine in 1,713 Caucasians and seven in 168 African-Americans showed these low levels of TPI activity. One possible explanation is that complete TPI deficiency is an embryolethal condition. In other words, if complete TPI deficiency is inherited at conception, this embryo is miscarried before the mother even knows that conception had occurred.

All of the mutations in the gene responsible for the production of TPI are expressed as dominant traits. This means that a child can inherit this condition from just one of his or her parents. Also, if one child has been born affected with TPI deficiency, the likelihood that a second child, of the same parents, will also be affected is 50%. This likelihood is increased to 75% if both parents carry the defective gene.

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Signs and symptoms

TPI deficiency affects primarily the circulatory and nervous systems. Disorders of the circulatory system include at least four separate forms of anemia (a lack of properly functioning red blood cells) that cause a lack of oxygen transport to the tissues and organs of the body. Disorders of the nervous system include developmental retardation and degenerative neurologic disorder with spasticity, a condition in which the nervous system progressively degenerates and the affected person suffers from spasticity similar to that seen in people with multiple sclerosis.

Because of the malformations of the red blood cells in TPI deficiency affected individuals, the liver, the organ that is responsible for cleaning the blood, often becomes overworked. This causes jaundice (an abnormal yellowing of the skin and the whites of the eyes). Heart failure is also quite common and is often the cause of death in TPI deficiency patients.

People affected with TPI deficiency are generally highly susceptible to recurrent infections. This tendency is believed to be due to a depression of the immune system caused by improper blood function.

Diagnosis

If a family history of the disease leads to suspicion, TPI deficiency can be detected prenatally by a test of umbilical cord blood. A device recognized by the U. S. Food and Drug Administration is available to measure the activity of TPI on red blood cells taken in a sample. This device provides a definitive test for TPI deficiency. A blood test indicating extremely elevated levels of DHAP is also indicative of TPI deficiency.

Another blood test that can be performed is an autohemolysis test. This test allows TPI deficiency to be differentially diagnosed from certain other enzymatic deficiencies. In this test, samples of blood are drawn and incubated at body temperature for 48 hours. After this time, the amount of breakdown of the red blood cells is recorded. One sample is left untreated, one sample has added glucose, and a third sample has added ATP. If the untreated sample shows higher than normal breakdown of the red blood cells, but those samples treated with glucose or ATP show a lessened breakdown of red blood cells, this is indicative of TPI deficiency. If glucose, but not ATP, slows the breakdown of the red blood cells, this indicates a diagnosis of G6PD deficiency. If ATP, but not glucose, slows the breakdown of the red blood cells, this indicates a diagnosis of pyruvate kinase deficiency. G6PD and pyruvate kinase are

K E Y T E R M S

Anemia—A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.

Jaundice—Yellowing of the skin or eyes due to excess of bilirubin in the blood.

Thermolabile—Heat-sensitive. A thermolabile protein is a protein that easily loses its shape when heated even only slightly.

Transversion—A genetic term referring to a specific substitution of one base pair for another. There are only four possible tranversions: guanine for cytosine, cytosine for guanine, adenine for thymine, or thymine for adenine.

Triose phosphate isomerase—Abbreviated TPI, this is the enzyme responsible for the conversion of dihydroxyacetone phosphate (DHAP) into D- glyceraldehyde-3-phosphate (GAP). DHAP and GAP are the two major products of a step in the multi-step process that converts glucose into ATP to supply the body with the energy it needs to sustain itself. Only GAP can continue in this process, but DHAP is produced in much higher quantities. People with TPI deficiency cannot change DHAP into GAP as efficiently as unaffected people, resulting in insufficient amounts of ATP from glucose to maintain normal cell function.

two other enzymes involved in the breakdown of glucose to pyruvate to ATP.

Treatment and management

No treatment is currently available for TPI deficiency. Studies are ongoing to determine the feasibility of bone marrow transplants and enzyme replacement therapies. In 1999, TPI deficiency was corrected in a four- year-old boy by an enzyme replacement blood transfusion treatment. However, due to the temporary nature of the observed corrections in the biochemistry, it was concluded that a sustained reversal of the symptoms of TPI deficiency would require a continuous delivery of an active form of the TPI enzyme.

Prognosis

There are only two reported cases of TPI deficiency affected individuals living beyond the age of six. These

deficiency isomerase phosphate Triose

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Malformations of the red blood cells in triose phosphate isomerase deficiency cause the liver, the organ responsible for cleaning the blood, to become overworked. This results in jaundice, an abnormal yellowing of the skin and the whites of the eyes. (Custom Medical Stock Photo, Inc.)

are a set of Hungarian brothers, one who did not develop neurological symptoms of TPI deficiency until 1980, at the age of 12, and an older brother, who was 30 in 2001, who has no neurological symptoms and suffers only from anemia. Enzyme replacement therapy and/or bone marrow transplantation may eventually prove to be effective means of treating TPI deficiency, and improve survival rates for this rare genetic disorder.

Resources

PERIODICALS

Ationu, A. “Toward Enzyme-replacement Treatment in Triosephosphate Isomerase Deficiency.” Lancet (April 1999): 1155-56.

Humphries, A., et al. “Ancestral Origin of Variation in the Triosephosphate Isomerase Gene Promoter.” Human Genetics (June 1999): 486-91.

Pekrun, A., et al. “Triosephosphate Isomerase Deficiency: Biochemical and Molecular Genetic Analysis for Prenatal Diagnosis.” Clinical Genetics (April 1995): 175-9.

Watanabe, M., B. Zingg, and H. Mohrenweiser. “Molecular Analysis of a Series of Alleles in Humans with Reduced Activity at the Triosephosphate Isomerase Locus.”

American Journal of Human Genetics (February 1996): 308-16.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

James Stewardson TPI Trust. http://members.gconnect.com/ users/tpi/top.htm (February 23, 2001).

“Triosephosphate Isomerase 1.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/ entrez/dispomim.cgi?id=190450 (February 23, 2001).

Paul A. Johnson

Trisomy see Chromosomal abnormalities

Trisomy 13 see Patau syndrome

I Trisomy 18

Definition

Trisomy 18 is a genetic syndrome of multiple congenital anomalies and severe to profound mental retardation. It is caused by the presence of an extra chromosome 18 in some or all of the cells of the body. Babies with the condition usually do not survive past several months of age. Trisomy 18 in the embryo/fetus is also a common chromosomal cause of pregnancy loss.

Description

Chromosomes are the microscopic structures inside cells that carry the genes. The genetic material inside each cell contains all of the instructions the body needs to develop and function normally. Humans have 23 different pairs of chromosomes. Chromosomes 1-22 are numbered from largest to smallest, and as a group are known as the autosomes. The last pair of chromosomes are designated X and Y, and are known as the sex chromosomes— females have two X chromosomes and males have one X and one Y. Other than sperm and eggs, each cell in the body normally has 46 chromosomes—a pair of each of the autosomes plus two sex chromosomes. In order for normal development and functioning to occur, chromosomes and genes must be present in the correct quantity and in the correct proportion to each other. Too much or too little genetic material usually causes serious problems.

The term euploid means “good set,” and is used to designate a full set of 46 chromosomes. A cell is aneuploid (“not a good set”) if it has any number of chromosomes other than 46. A trisomy is one type of aneuploidy, and refers to a cell that contains three of the same chromosome. Trisomy 18, then, refers to three chromosomes 18. After Down syndrome (trisomy 21), trisomy 18 is the most common autosomal aneuploid condition seen in

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live-born babies. Trisomy 18 is also known as Edwards syndrome.

Edwards syndrome is comprised of a specific but broad pattern of multiple congenital anomalies and mental retardation. Babies with Edwards syndrome tend to have similar physical features and medical problems because they all have the same genetic imbalance—an extra copy of the genes on chromosome 18. The physical anomalies associated with Edwards syndrome involve nearly every organ and system of the body. However, some anomalies occur more often than others, such as those of the heart, kidney, brain, skeleton, and craniofacial (head and face) area. The birth defects are typically serious and, combined with the large number of anomalies possible, result in a high mortality rate. About 60% of newborns with Edwards syndrome die within the first week, and 80% do not survive past one month of age. Even those with Edwards syndrome who live longer will have severe to profound mental retardation and chronic medical problems, necessitating involved care and monitoring throughout their lives.

Genetic profile

Edwards syndrome occurs in three different forms: full trisomy 18, mosaic trisomy 18, and partial trisomy 18. Before each of these is described, however, it is helpful to review the basics of normal reproduction and early embryonic development. As noted, cells in the body normally contain 46 chromosomes in 23 pairs, except sperm in males and eggs in females, which contain one chromosome of each pair, or 23 total. Meiosis is the process by which sperm and eggs, collectively known as gametes, are produced. In normal meiosis, the 46 chromosomes line up in pairs in the middle of a cell, and the cell divides down the middle separating each pair of chromosomes. When a sperm fertilizes an egg at conception, the 23 chromosomes from each gamete combine. A process of repeated chromosome duplication followed by cell division, known as mitosis, then begins. A cell that goes through mitosis produces two new cells, each with 46 chromosomes. A developing human is called an embryo during the eight weeks after conception, and a fetus for the remainder of pregnancy.

Full trisomy 18

Occasionally, chromosomes of a single pair do not separate during meiosis, an abnormal process known as nondisjunction. The result is one gamete with 24 chromosomes and another with 22. If a gamete with 24 chromosomes results in conception with a normal counterpart, an embryo with 47 chromosomes is produced. In most cases, all cells in the body will then have

K E Y T E R M S

Aneuploidy—An abnormal number of chromosomes in a cell. Trisomy 18 and trisomy 13 are examples of aneuploid conditions.

Chromosome translocation—The exchange of genetic material between chromosomes, which can lead to extra or missing genetic material.

Geneticist—A specialist (M.D. or Ph.D.) who has training and certification in diagnosing, managing, and counseling individuals/families with genetic disorders. Genetics counselors hold a master’s degree in medical genetics, and provide many of the same services as geneticists.

Meiosis—The process in which a cell in the testes or ovaries undergoes chromosome separation and cell division to produce sperm or eggs.

Mitosis—The process by which a somatic cell—a cell not destined to become a sperm or egg— duplicates its chromosomes and divides to produce two new cells.

Mosaicism—A genetic condition resulting from a mutation, crossing over, or nondisjunction of chromosomes during cell division, causing a variation in the number of chromosomes in the cells.

Neonatologist—A physician (pediatrician) who has special training in the care of newborns (neonates).

Nondisjunction—Non-separation of a chromosome pair, during either meiosis or mitosis.

Perinatologist—A physician (obstetrician) who has special training in managing difficult pregnancies. Some prenatal tests, such as chorionic villus sampling and level II ultrasound, are performed primarily by perinatologists.

Trisomy—The condition of having three identical chromosomes, instead of the normal two, in a cell.

47 chromosomes, a condition known as full trisomy 18 (when referring to an individual with the disorder, unless otherwise specified, the term “trisomy 18” implies a full trisomy, whereas Edwards syndrome may refer to any of the forms).

Nondisjunction of two chromosomes 18 during the formation of an egg or sperm is by far the most common cause of Edwards syndrome. Nondisjunction is a chance occurrence, with no known causative or preventive factors. The incidence of nondisjunction does increase,

18 Trisomy

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