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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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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-versus- host 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.

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 77to 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.

TABLE 1

HLA disease associations

Disease

MHC allele

Approximate relative risk

Ankylosing spondylitis

B27

77–90

Celiac disease

DR3 + DR7

5–10

Diabetes, Type 1

DR3

5

Diabetes, Type 1

DR4

5–7

Diabetes, Type 1

DR3 + DR4

20–40

Graves disease

DR3

5

Hemochromatosis

A3

6–20

Lupus

DR3

1–3

Multiple sclerosis

DR2

2–4

Myasthenia gravis

B8

2.5–4

Psoriasis vulgaris

Cw6

8

Rheumatoid arthritis

DR4

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 under-

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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 Manualhttp://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

I Malignant hyperthermia

Definition

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 tem-

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

sevoflurane

desflurane

methoxyflurane

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 mus-

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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.

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.

K E Y T E R M S

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

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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 their susceptibility may not be recognized even if they do have one or more surgeries. Once MH susceptibility is diagnosed in an individual, however, it is important for his or her family members to know they also have a risk for MH susceptibility, since it is a dominant condition. This means that anyone with a family member who has MH susceptibility should tell their doctor about their family history. Since MH may go unrecognized, it is important that anyone who has had a close relative die from anesthesia notify the anesthesiologist before any type of surgery is planned. People with a family history of MH susceptibility may choose to meet with a genetic counselor to discuss the significance of their family history as well. In addition, relatives of an affected person may consider having a test to see if they also inherited MH susceptibility.

Although there are many people who have the same symptoms of MH when exposed to trigger drugs, genetic research has shown that there are probably many genes, located on different chromosomes, that can all lead to MH susceptibility. This indicates that there is genetic heterogeneity among different families with MH susceptibility, meaning that different genes can lead to the same or similar disease among different families. As of March 2001, researchers identified six different types of MH susceptibility. Although specific genes have been discovered for some of these types, others have been linked only to specific chromosomal regions.

Genetic classification of malignant hyperthermia:

MHS1—Located on chromosome 19q13.1. Specific gene called RYR1. Gene creates the RYR protein.

MHS2—Located on chromosome 17q11.2-24. Suspected gene called SCN4A.

MHS3—Located on chromosome 7q21-22. Suspected gene called CACNA2DI. Gene creates part of the DHPR protein called the alpha 2/delta subunit.

MHS4—Located on chromosome 3q13.1. Specific gene and protein unknown.

MHS5—Located on chromosome 1q32. Specific gene called CACNA1S. Gene creates part of the DHPR protein called the alpha 1 subunit.

MHS6—Located on chromosome 5p. Specific gene and protein unknown.

Over half of all families with MH susceptibility are believed to have MHS1 (i.e. have changes in the RYR1 gene), while the rest have MHS2, MHS3, MHS4, MHS5, or MHS6. However, as of January 2000, only 20% of all families tested had specific genetic changes identified in the RYR1 gene. This is because there are many different types of genetic changes in the gene that can all lead to MH susceptibility, and many families have changes that are unique. As a result, genetic testing of the RYR1 gene is complicated, time consuming, and often cannot locate all possible genetic changes. In addition, genetic testing for families may become more complex as knowledge about MH grows. This issue was discussed in an article published by researchers in July 2000. The authors explained that although MH susceptibility has typically been described as an autosomal dominant trait caused by a single gene that is passed from one generation to the next, they believe MH susceptibility may actually depend upon various genetic changes that occur in more than one gene. Further research may clarify this issue in the future.

While specific genes have been identified for some of the MH susceptibility types (i.e. RYR1 and DHPR alpha 1 subunit), not all changes in these genes lead specifically to MH susceptibility. For example, although at least 20 different genetic changes have been identified in the RYR1 gene that can lead to MH susceptibility, some people who have certain types of these changes actually have a different genetic condition that affects the muscles called central core disease (CCD). Infants with this autosomal dominant condition typically have very poor muscle tone (i.e. muscle tension) as well as an increased susceptibility to MH. Among families who have CCD, there are some individuals who do not have the typical muscle changes, but have MH susceptibility instead. Hopefully, future research will help scientists understand why the same genetic change in the RYR1 gene can cause different symptoms among people belonging to the same family.

Demographics

The exact number of individuals who are born with a genetic change that causes MH susceptibility is not known. Until genetic research and genetic testing improves, this number will likely remain unclear. However, it is estimated that internationally one in 50,000 people who are exposed to anesthesia develop an MH reaction. Among children, it is estimated that one in 5,000 to one in 15,000 develop MH symptoms when exposed to anesthesia. MH has been seen in many countries, although there are some geographic areas where it

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occurs more often in the local populations, including parts of Wisconsin, North Carolina, Austria, and Quebec.

Signs and symptoms

Although the specific symptoms of malignant hyperthermia can vary, the most common findings include:

stiffness/spasms of jaw muscles and other muscles

rapid breathing, causing decreased oxygen and increased carbon dioxide in the blood

rapid or irregular heartbeat

high body temperature (over 110°F)

muscle breakdown (may cause dark or cola-colored urine)

internal bleeding, kidney failure, brain damage, or death (if not treated successfully)

Diagnosis

The diagnosis of MH susceptibility can be made before or during a reaction to a triggering drug. Ideally, the diagnosis is made before a susceptible individual is exposed and/or develops a reaction. This is possible for people who learn they have an increased chance for MH because they have a relative with MH susceptibility. Testing these individuals requires a surgical procedure called a muscle biopsy, in which a piece of muscle tissue is removed from the body (usually from the thigh). Safe (i.e. non-triggering) anesthetics are used during the procedure. The muscle is taken to a laboratory and is exposed to halothane (a triggering anesthetic) and caffeine, both of which cause any muscle tissue to contract, or tighten. Thus the test is called the caffeine halothane contracture test (CHCT). Muscle tissue taken from individuals with MH susceptibility is more sensitive to caffeine and halothane, causing it to contract more strongly than normal muscle tissue from non-susceptible people. This type of test is a very accurate way to predict whether a person has MH susceptibility or not. However, the test does require surgery, time to recover (typically three days), and it is expensive (approximately $2,500). In the United States, many insurance companies will pay for the testing if it is needed. Although the test is not available in every state or country, there are at least 40 medical centers worldwide that can perform the test.

Unfortunately, not all MH susceptible people will learn from their family histories that they have an increased risk for MH before they are exposed to a trigger drug. For these individuals, the diagnosis of MH susceptibility is often made during surgery by the anesthesiologist (a physician specializing in anesthesia)

who is providing the anesthesia medications. Other health care specialists also may notice symptoms of MH during or after surgery. Symptoms such as rapid breathing, rapid heart rate, and high body temperature can usually be detected with various machines or devices that examine basic body functions during surgery. Muscle stiffness of the jaw, arms, legs, stomach and chest may be noticed as well. These symptoms may happen during surgery or even several hours later. If the diagnosis is made during or after surgery, immediate treatment is needed to prevent damage to various parts of the body or death. If a person has a suspicious reaction to anesthesia, he or she may undergo a muscle biopsy to confirm MH susceptibility at a later date.

In spite of the fact that a number of important genes and genetic regions associated with MH susceptibility have been identified, testing a person’s DNA for all of the possible changes that may cause this condition is not easily done for affected individuals and their families. As of March 2001, existing genetic testing identifies some changes that have been seen among families with MHS1 and MHS6. Research studies may provide information for families with MHS2, MHS3, MHS4, and MHS5 as well. Sometimes the testing requires DNA from only one affected person, but in other cases, many samples are needed from a variety of family members. However, until genetic technology improves, the contracture test that is done on muscle tissue will likely remain the “gold standard” for diagnosis of MH susceptibility.

Treatment and management

The early identification of an MH episode allows for immediate treatment with an “antidote” called dantrolene sodium. This medication prevents the release of calcium from the sarcoplasmic reticulum, which decreases muscle stiffness and energy production in the cells. If hyperthermia develops, the person’s body can be cooled with ice. In addition, the anesthesiologist will change the anesthetic from a trigger drug to a non-trigger drug. Immediate treatment is necessary to prevent serious illness and/or death.

Once a person with definite or suspected MH susceptibility is diagnosed (by an MH episode, muscle biopsy, or family history), prevention of an MH episode is possible. There are many types of non-triggering anesthetic drugs and muscle relaxants that can be used during surgical procedures. The important first step in this process is for people with known or suspected MH susceptibility to talk with their doctors before any surgery, so that only nontriggering drugs are used. People with definite or suspected MH susceptibility should always carry some form of medical identification that describes their diagnosis in

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case emergency surgery is needed. The Malignant Hyperthermia Association of the United States provides wallet-sized emergency medical ID cards for its members.

Prognosis

Early diagnosis and treatment of MH episodes with dantrolene sodium has dramatically improved the prognosis for people who develop MH during or just after surgery. When the condition was first recognized in the 1960s, no real treatment (other than cooling the person’s body) was available, and only 20–30% of people who developed MH survived. When the antidote (dantrolene sodium) became available in 1979, the survival rate increased to 70–80%. However, 5–10% of people who develop MH after exposure to a trigger drug still may die even with proper medication and care. Among those who do survive, some are disabled due to kidney, muscle, or brain damage. The best prognosis exists for people with definite or suspected MH susceptibility who are able to prevent exposures to trigger drugs by discussing their history with their doctors. Improved genetic testing in the future may help identify most or all people with inherited MH susceptibility, so they too may prevent exposures that could trigger MH episodes.

Resources

BOOKS

Hopkins, Philip M., and F. Richard Ellis, eds. Hyperthermic and Hypermetabolic Disorders: Exertional Heat Stroke, Malignant Hyperthermia and Related Syndromes. Port Chester, NY: Cambridge University Press, 1996.

Morio, Michio, Haruhiko Kikuchi, and O. Yuge, eds. Malignant Hyperthermia: Proceedings of the 3rd International Symposium on Malignant Hyperthermia, 1994. Secaucus, NJ: Springer-Verlag, 1996.

Ohnishi, S. Tsuyoshi, and Tomoko Ohnishi, eds. Malignant Hyperthermia: A Genetic Membrane Disease. Boca Raton, FL: CRC Press, 1994.

PERIODICALS

Denborough, Michael. “Malignant hyperthermia.” The Lancet 352, no. 9134 (October 1998): 1131–36.

Hopkins, P.M. “Malignant Hyperthermia: Advances in clinical management and diagnosis.” British Journal of Anesthesia

85, no. 1 (2000): 118–28.

Jurkat-Rott, Karin, Tommie McCarthy, and Frank LehmannHorn. “Genetics and Pathogenesis of Malignant Hyperthermia.” Muscle & Nerve 23 (January 2000): 4–17.

ORGANIZATIONS

Malignant Hyperthermia Association of the United States. PO Box 1069, 39 East State St., Sherburne, NY 13460. (800) 98-MHAUS. http://www.mhaus.org .

WEBSITES

Larach, Marilyn Green, MD, FAAP. “Making anesthesia safer: Unraveling the malignant hyperthermia puzzle.” Federation of American Societies for Experimental Biology (FASEB). http://www.faseb.org/opar/mh/ .

“Malignant hyperthermia.” UCLA Department of Anesthesiology. http://www.anes.ucla.edu/dept/mh.html .

Pamela J. Nutting, MS, CGC

Manic-depressive psychosis see Bipolar disorder

I Mannosidosis

Definition

Mannosidosis is a rare inherited disorder, an inborn error of metabolism, that occurs when the body is unable to break down chains of a certain sugar (mannose) properly. As a result, large amounts of sugar-rich compounds build up in the body cells, tissues, and urine, interfering with normal body functions and development of the skeleton.

Description

Mannosidosis develops in patients whose genes are unable to make an enzyme required by lysosomes (structures within the cell where proteins, sugars, and fats are broken down and then released back into the cell to make other molecules). Lysosomes need the enzyme to break down, or degrade, long chains of sugars. When the enzyme is missing and the sugar chains are not broken down, the sugars build up in the lysosomes. The lysosomes swell and increase in number, damaging the cell. The result is mannosidosis.

The enzyme has two forms: alpha and beta. Similarly, the disorder mannosidosis has two forms: alpha-mannosidosis (which occurs when the alpha form of the enzyme is missing) and beta-mannosidosis (which occurs when the beta form of the enzyme is missing). Production of each form of the enzyme is controlled by a different gene.

First described in 1967, alpha-mannosidosis is classified further into two types. Infantile (or Type I) alphamannosidosis is a severe disorder that results in mental retardation, physical deformities, and death in childhood. Adult (or Type II) alpha-mannosidosis is a milder disorder in which mental retardation and physical deformities develop much more slowly throughout the childhood and teenage years.

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Beta-mannosidosis was identified nearly 20 years later in 1986. Patients with this form of the disorder are also mentally retarded but over a wide range of severity, from mild to extreme. Beta-mannosidosis is not well understood, in part because it is such a rare disease. It was discovered only because researchers searched for it: a deficiency of the beta form of the enzyme was known to cause disease in animals.

Genetic profile

The two forms of mannosidosis, alpha and beta, are caused by changes on two different genes. Mutations in the gene MANB, on chromosome 19, result in alphamannosidosis. This gene is also known as MAN2B1 or LAMAN. Defects in MANB cause alpha-mannosidosis in both infants and adults.

Beta-mannosidosis is caused by mutations in the gene MANB1 (also called MANBA). This gene is on chromosome 4.

Both genes, MANB and MANB1, are inherited as autosomal recessive traits. This means that if a man and woman each carry one defective gene, then 25% of their children are expected to be born with the disorder. Each gene is inherited separately from the other.

Demographics

Mannosidosis is a rare disorder, occurring in both men and women. The disorder does not affect any particular ethnic group but rather appears in a broad range of people. Alpha-mannosidosis has been studied in Scandinavian, Western and Eastern European, North American, Arabian, African, and Japanese populations. Researchers have identified beta-mannosidosis in European, Hindu, Turkish, Czechoslovakian, JamaicanIrish, and African families.

Signs and symptoms

The various forms and types of mannosidosis all have one symptom in common: mental retardation. Other signs and symptoms vary.

Infants with alpha-mannosidosis appear normal at birth, but by the end of their first year, they show signs of mental retardation, which rapidly gets worse. They develop a group of symptoms that includes dwarfism, shortened fingers, and facial changes. In these children, the bridge of the nose is flat, they have a prominent forehead, their ears are large and low set, they have protruding eyebrows, and the jaw juts out. Other symptoms include lack of muscle coordination, enlarged spleen and liver, recurring infections, and cloudiness in the back of the eyeball, which is normally clear. These patients often

K E Y T E R M S

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Lysosomal storage disease—A category of disorders that includes mannosidosis.

Lysosome—Membrane-enclosed compartment in cells, containing many hydrolytic enzymes; where large molecules and cellular components are broken down.

Mannose—A type of sugar that forms long chains in the body.

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.

have empty bubbles in their white blood cells, a sign that sugars are being stored improperly.

The adult form occurs in 10–15% of the cases of alpha-mannosidosis. The symptoms in adults are the same as in infants, but they are milder and develop more slowly. Patients with adult alpha-mannosidosis are often normal as babies and young children, when they develop mentally and physically as expected. In their childhood or teenage years, however, mental retardation and physical symptoms become evident. These patients may also lose their hearing and have pain in their joints.

Beta-mannosidosis is characterized by symptoms that range from mild to severe. In all patients, however, the most frequent signs are mental retardation, lung infections, and hearing loss with speech difficulties. In mild cases, patients have red, wart-like spots on their skin. In severe cases, patients may have multiple seizures, and their arms and legs may be paralyzed. Because the symptoms of beta-mannosidosis vary so greatly, researchers suggest that the disorder may frequently be misdiagnosed.

Diagnosis

All types of mannosidosis are tested in the same way. In an infant, child, or adult, doctors can check the patient’s urine for abnormal types of sugar. They may also test the patient’s blood cells to learn if the enzyme is present.

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If doctors suspect that a pregnant woman may be carrying a child with mannosidosis, they can test cells in the fluid surrounding the baby for enzyme activity.

Treatment and management

There is no known treatment for mannosidosis. The symptoms—mental retardation and skeletal abnormali- ties—are managed by supportive care, depending on the severity. Patients with adult alpha-mannosidosis and beta-mannosidosis may show mild mental retardation or behavior problems (such as depression or aggression) and may be mainstreamed into society. Others may require institutionalization. Skeletal abnormalities may require surgery to correct them, and recurring infections are treated with antibiotics.

Research with animals suggests that mannosidosis can be treated by placing healthy cells without defective genes into the animals’ bones (bone marrow transplant). Other researchers have successfully treated mannosidosis in animals by inserting healthy genes into the unborn offspring of a pregnant animal. These treatments have not been proven on humans, however.

Prognosis

The future for patients with mannosidosis varies with the form of their disorder. For infants with alphamannosidosis, death is expected between ages three and 12 years. For infants with beta-mannosidosis, death will come earlier, by the time they are 15 months old.

Patients with mild forms of alphaand beta-man- nosidosis often survive into adulthood, but their lives are complicated by mental retardation and physical deterioration. They will generally die in their early or middle years, depending on the severity of their disorder.

Resources

BOOKS

Thomas, George. “Disorders of Glycoprotein Degradation: Alpha-Mannosidosis, Beta-Mannosidosis, Fucosidosis, and Sialidosis.” In The Metabolic and Molecular Bases of Inherited Disease. Scriver, Charles R., et al., ed. Vol. II, 8th ed. New York: McGraw-Hill, 2001.

PERIODICALS

Alkhayat, Aisha H., et al. “Human Beta-Mannosidase cDNA Characterization and First Identification of a Mutation Associated with Human Beta-Mannosidosis.” Human Molecular Genetics 7, no. 1 (1998): 75–83.

Berg, Thomas, et al. “Spectrum of Mutations in AlphaMannosidosis.” American Journal of Human Genetics 64 (1999): 77–88.

Michalski, Jean-Claude, and Andre Klein. “Glycoprotein Lysosomal Storage Disorders: Alphaand Beta-

Mannosidosis, Glucosidosis, and Alpha-N-Acetylgalacto- saminidase Deficiency.” Biochimica et Biophysica Acta:

Molecular Basis of Disease 1455, no. 2–3 (October 8, 1999): 69–84.

ORGANIZATIONS

Arc (a National Organization on Mental Retardation). 1010 Wayne Ave., Suite 650, Silver Spring, MD 20910. (800) 433-5255. http://www.thearclink.org .

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327.http://www.climb.org.uk .

International Society for Mannosidosis and Related Diseases. 3210 Batavia Ave., Baltimore, MD 21214. (410) 2544903. http://www.mannosidosis.org .

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. info @mpssociety.org. http://www.mpssociety.org .

WEBSITES

Web Site for Rare Genetic Diseases in Children: Lysosomal Storage Diseases. http://mcrcr2.med.nyu.edu/murphp01/ lysosome/lysosome.htm .

Linnea E. Wahl, MS

I Marfan syndrome

Definition

Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of the patient’s eyes, cardiovascular system, and musculoskeletal system. It is named for the French pediatrician, Antoine Marfan (1858-1942), who first described it in 1896. Marfan syndrome is sometimes called arachnodactyly, which means “spider-like fingers” in Greek, since one of the characteristic signs of the disease is disproportionately long fingers and toes. It is estimated that one person in every 3,000-5,000 has Marfan syndrome, or about 50,000 people in the United States. Marfan syndrome is one of the more common inheritable disorders.

Description

Marfan syndrome affects three major organ systems of the body: the heart and circulatory system, the bones and muscles, and the eyes. The genetic mutation responsible for Marfan was discovered in 1991. It affects the body’s production of fibrillin, which is a protein that is an important part of connective tissue. Fibrillin is the primary component of the microfibrils that allow tissues to stretch repeatedly without weakening. Because the

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patient’s fibrillin is abnormal, his or her connective tissues are looser than usual, which weakens or damages the support structures of the entire body.

The most common external signs associated with Marfan syndrome include excessively long arms and legs, with the patient’s arm span being greater than his or her height. The fingers and toes may be long and slender, with loose joints that can bend beyond their normal limits. This unusual flexibility is called hypermobility. The patient’s face may also be long and narrow, and he or she may have a noticeable curvature of the spine. It is important to note, however, that Marfan patients vary widely in the external signs of their disorder and in their severity; even two patients from the same family may look quite different. Most of the external features of Marfan syndrome become more pronounced as the patient gets older, so that diagnosis of the disorder is often easier in adults than in children. In many cases, the patient may have few or very minor outward signs of the disorder, and the diagnosis may be missed until the patient develops vision problems or cardiac symptoms.

Marfan syndrome by itself does not affect a person’s intelligence or ability to learn. There is, however, some clinical evidence that children with Marfan have a slightly higher rate of attention deficit hyperactivity disorder (ADHD) than the general population. In addition, a child with undiagnosed nearsightedness related to Marfan may have difficulty seeing the blackboard or reading printed materials, and thus do poorly in school.

K E Y T E R M S

Arachnodactyly—A condition characterized by abnormally long and slender fingers and toes.

Ectopia lentis—Dislocation of the lens of the eye. It is one of the most important single indicators in diagnosing Marfan syndrome.

Fribrillin—A protein that is an important part of the structure of the body’s connective tissue. In Marfan’s syndrome, the gene responsible for fibrillin has mutated, causing the body to produce a defective protein.

Hypermobility—Unusual flexibility of the joints, allowing them to be bent or moved beyond their normal range of motion.

Kyphosis—An abnormal outward curvature of the spine, with a hump at the upper back.

Pectus carinatum—An abnormality of the chest in which the sternum (breastbone) is pushed outward. It is sometimes called “pigeon breast.”

Pectus excavatum—An abnormality of the chest in which the sternum (breastbone) sinks inward; sometimes called “funnel chest.”

Scoliosis—An abnormal, side-to-side curvature of the spine.

Genetic profile

Marfan syndrome is caused by a single gene for fibrillin on chromosome 15, which is inherited in most cases from an affected parent. Between 15% and 25% of cases result from spontaneous mutations. Mutations of the fibrillin gene (FBNI) are unique to each family affected by Marfan, which makes rapid genetic diagnosis impossible, given present technology. The syndrome is an autosomal dominant disorder, which means that someone who has it has a 50% chance of passing it on to any offspring.

Another important genetic characteristic of Marfan syndrome is variable expression. This term means that the mutated fibrillin gene can produce a variety of symptoms of very different degrees of severity, even in members of the same family.

Demographics

Marfan syndrome affects males and females equally, and appears to be distributed equally among all races and ethnic groups. The rate of mutation of the fibrillin gene, however, appears to be related to the age of the patient’s

father; older fathers are more likely to have new mutations appear in chromosome 15.

Signs and symptoms

Cardiac and circulatory abnormalities

The most important complications of Marfan syndrome are those affecting the heart and major blood vessels; some are potentially life-threatening. About 90% of Marfan patients will develop cardiac complications.

Aortic enlargement. This is the most serious potential complication of Marfan syndrome. Because of the abnormalities of the patient’s fibrillin, the walls of the aorta (the large blood vessel that carries blood away from the heart) are weaker than normal and tend to stretch and bulge out of shape. This stretching increases the likelihood of an aortic dissection, which is a tear or separation between the layers of tissue that make up the aorta. An aortic dissection usually causes severe pain in the abdomen, back, or chest, depending on the section of the aorta that is affected. Rupture of the aorta is a

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medical emergency requiring immediate surgery and medication.

Aortic regurgitation. A weakened and enlarged aorta may allow some blood to leak back into the heart during each heartbeat; this condition is called aortic regurgitation. Aortic regurgitation occasionally causes shortness of breath during normal activity. In serious cases, it causes the left ventricle of the heart to enlarge and may eventually lead to heart failure.

Mitral valve prolapse. Between 75% and 85% of patients with Marfan syndrome have loose or “floppy” mitral valves, which are the valves that separate the chambers of the heart. When these valves do not cover the opening between the chambers completely, the condition is called mitral valve prolapse. Complications of mitral valve prolapse include heart murmurs and arrhythmias. In rare cases, mitral valve prolapse can cause sudden death.

Infective endocarditis. Infective endocarditis is an infection of the endothelium, the tissue that lines the heart. In patients with Marfan syndrome, it is the abnormal mitral valve that is most likely to become infected.

Other complications. Some patients with Marfan syndrome develop cystic disease of the lungs or recurrent spontaneous pneumothorax, a condition in which air accumulates in the space around the lungs. Many patients will also eventually develop emphysema.

Musculoskeletal abnormalities

Marfan syndrome causes an increase in the length of the patient’s bones, with decreased support from the ligaments that hold the bones together. As a result, the patient may develop various deformities of the skeleton or disorders related to the relative looseness of the ligaments.

Disorders of the spine

Scoliosis. Scoliosis, or curvature of the spine, is a disorder in which the vertebrae that make up the spine twist out of line from side to side into an S-shape or a spiral. It is caused by a combination of the rapid growth of children with Marfan, and the looseness of the ligaments that help the spine to keep its shape.

Kyphosis is an abnormal outward curvature of the spine, sometimes called hunchback when it occurs in the upper back. Patients with Marfan may develop kyphosis either in the upper (thoracic) spine or the lower (lumbar) spine.

Spondylolisthesis. Spondylolisthesis is the medical term for a forward slippage of one vertebra on the one below it. It produces an ache or stiffness in the lower back.

Dural ectasia. The dura is the tough, fibrous outermost membrane covering the brain and the spinal cord. The weak dura in patients with Marfan swells or bulges under the pressure of the spinal fluid. This swelling is called ectasia. In most cases, dural ectasia occurs in the lower spine, producing low back ache, a burning feeling, or numbness or weakness in the legs.

Disorders of the chest and lower body

Pectus excavatum. Pectus excavatum is a malformation of the chest in which the patient’s breastbone, or sternum, is sunken inward. It can cause difficulties in breathing, especially if the heart, spine, and lung have been affected by Marfan syndrome. It may also cause concerns about appearance.

Pectus carinatum. In other patients with Marfan syndrome the sternum is pushed outward and narrowed. Although pectus carinatum does not cause breathing difficulties, it can cause embarassment about appearance. A few patients may have a pectus excavatum on one side of their chest and a pectus carinatum on the other.

Foot disorders. Patients with Marfan syndrome are more likely to develop pes planus (flat feet) or so-called “claw” or “hammer” toes than people in the general population. They are also more likely to have chronic pain in their feet.

Protrusio acetabulae. The acetabulum is the socket of the hip joint. In patient’s with Marfan syndrome, the acetabulum becomes deeper than normal during growth for reasons that are not yet understood. Although protrusio acetabulae does not cause problems during childhood and adolescence, it can lead to a painful form of arthritis in adult life.

Disorders of the eyes and face

Although the visual problems related to Marfan syndrome are rarely life-threatening, they are important in that they may be the patient’s first indication of the disorder. Eye disorders related to the syndrome include the following:

Myopia (nearsightedness). Most patients with Marfan develop nearsightedness, usually in childhood.

Ectopia lentis. Ectopia lentis is the medical term for dislocation of the lens of the eye. Between 65% and 75% of patients with Marfan have dislocated lenses. This condition is an important indication for diagnosis of the syndrome because there are relatively few other disorders that produce it.

Glaucoma. This condition is much more prevalent in patients with Marfan syndrome than in the general population.

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