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

Liver cancer

Laparoscopy

The doctor may also perform a laparoscopy to help in the diagnosis of liver cancer. A laparoscope is a small tube-shaped instrument with a light at one end. The doctor makes a small cut in the patient’s abdomen and inserts the laparoscope. A small piece of liver tissue is removed and examined under a microscope for the presence of cancer cells.

Treatment

Treatment of liver cancer is based on several factors, including the type of cancer (primary or metastatic); stage (early or advanced); the location of other primary cancers or metastases in the patient’s body; the patient’s age; and other coexisting diseases, including cirrhosis. Treatment options include surgery, radiation, and chemotherapy. At times, two or all three of these may be used together. For many patients, treatment of liver cancer is primarily intended to relieve the pain caused by the cancer but cannot cure it.

Surgery

The goal of surgery is to remove the entire tumor, curing liver cancer. However, few liver cancers in adults can be cured by surgery because they are usually too advanced by the time they are discovered. If the cancer is contained within one lobe of the liver, and if the patient does not have cirrhosis, jaundice, or ascites, surgery is the best treatment option. Patients who can have their entire tumor removed have the best chance for survival.

If the entire visible tumor can be removed, about 25% of patients will be cured. The operation that is performed is called a partial hepatectomy, or partial removal of the liver. The surgeon will remove either an entire lobe of the liver (a lobectomy) or cut out the area around the tumor (a wedge resection).

Doctors may also offer tumor embolization or ablation. Embolization involves killing a tumor by blocking its blood supply. Ablation is a method of destroying a tumor without removing it. One method of ablation, cryosurgery, involves freezing the tumor, thereby destroying it. In another method of ablation, ethanol ablation, doctors kill the tumor by injecting alcohol into it. As of 2001, a new method of ablation using high-energy radio waves is under development.

Chemotherapy

Chemotherapy involves using very strong drugs, taken by mouth or intravenously, to suppress or kill tumor cells. Chemotherapy also damages normal cells,

leading to side effects such as hair loss, vomiting, mouth sores, loss of appetite, and fatigue.

Some patients with incurable metastatic cancer of the liver can have their lives prolonged for a few months by chemotherapy. If the tumor cannot be removed by surgery, a tube (catheter) can be placed in the main artery of the liver and an implantable infusion pump can be installed (hepatic artery infusion). The pump allows much higher concentrations of cancer drugs to be carried directly to the tumor.

Hepatocellular carcinoma is resistant to most drugs. Specific drugs such as doxorubicin and cisplatin have been proven effective against this type of cancer. Systemic chemotherapy can also be used to treat liver cancer. Systemic chemotherapy does not, however, significantly lengthen the patient’s survival time.

Radiation therapy

Radiation therapy is the use of high-energy rays or x rays to kill cancer cells or to shrink tumors. In liver cancer, however, radiation is only able to give brief relief from some of the symptoms, including pain. Liver cancers are not sensitive to levels of radiation considered safe for surrounding tissues. Radiation therapy has not been shown to prolong the life of a patient with liver cancer.

Liver transplantation

Removal of the entire liver (total hepatectomy) and liver transplantation are used very rarely in treating liver cancer as of 1998. This is because very few patients are eligible for this procedure, either because the cancer has spread beyond the liver or because there are no suitable donors. Further research in the field of transplant immunology may make liver transplantation a possible treatment method for more patients in the future.

Future treatments

Gene therapy may be a future treatment for liver cancer. As of 2001, scientists are still investigating the possible use of gene therapy as a treatment for cancer. As of 2001, there is controversy surrounding experimentation with gene therapy on humans. As such, it may be years before science is able to create a clinically available gene therapy treatment.

Prognosis

Liver cancer has a very poor prognosis because it is often not diagnosed until it has metastasized. Fewer than 10% of patients survive three years after the initial diagnosis; the overall five-year survival rate for patients with

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hepatomas is around 4%. Most patients with primary liver cancer die within several months of diagnosis. Patients with liver cancers that metastasized from cancers in the colon live slightly longer than those whose cancers spread from cancers in the stomach or pancreas.

Prevention

There are no useful strategies at present for preventing metastatic cancers of the liver. Primary liver cancers, however, are 75–80% preventable. Current strategies focus on widespread vaccination for hepatitis B; early treatment of hereditary hemochromatosis; and screening of high-risk patients with alpha-fetoprotein testing and ultrasound examinations.

Lifestyle factors that can be modified in order to prevent liver cancer include avoidance of exposure to toxic chemicals and foods harboring molds that produce aflatoxin. In the United States laws protect workers from exposure to toxic chemicals. Changing grain storage methods in other countries may reduce aflatoxin exposure. Avoidance of alcohol and drug abuse is also very important. Alcohol abuse is responsible for 60–75% of cases of cirrhosis, which is a major risk factor for eventual development of primary liver cancer.

A vaccination for hepatitis B is now available. Widespread immunization prevents infection, reducing a person’s risk for liver cancer. Other protective measures against hepatitis include using protection during sex and not sharing needles. As of 2001, scientists have found that interferon injections may lower the risk for someone with hepatitis C or cirrhosis to develop liver cancer.

Resources

BOOKS

Blumberg, Baruch S. Hepatitis B and the Prevention of Cancer of the Liver. River Edge, N.J.: World Scientific Publishing Company, Inc., 2000.

Elmore, Lynne W., and Curtis C. Harris. “Hepatocellular Carcinoma.” In The Genetic Basis of Human Cancer. Ed. Bert Vogelstein and Kenneth Kinzler, 681–89. New York: McGraw-Hill, 1998.

Shannon, Joyce Brennfleck. Liver Disorders Source Book:

Basic Consumer Health Information about the Liver, and

How It Works. Detroit: Omnigraphics Inc., 2000.

PERIODICALS

Greenlee, Robert T., et al. “Cancer Statistics, 2001.” CA: A

Cancer Journal for Clinicians. 51 (January/February 2001): 15–36.

Hussain, S.A., et al. “Hepatocellular carcinoma.” Annals of Oncology 12 (February 2001): 161– 72.

Ogunbiyi, J. “Hepatocellular carcinoma in the developing world.” Seminars in Oncology 28 (April 2001): 179–87.

ORGANIZATIONS

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

American Liver Foundation. 75 Maiden Lane, Suite 603, New York, NY 10038. [phone] or [phone].http://www.liverfoundation.org .

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. [phone]. http://www.nci.nih

.gov .

Rebecca J. Frey, PhD

Judy C. Hawkins, MS

Long bone deficiencies associated with cleft lip/palate see Roberts SC phocomelia

I Long-QT syndrome

Definition

Long-QT syndrome is a family of genetic or acquired disorders that causes cardiac arrhythmias, irregularities in the electrical activity of the heart, that can lead to cardiac arrest and sudden death. The syndrome is characterized by a longer-than-normal QT interval on an electrocardiogram.

Description

Long-QT syndrome (LQTS) is one of the sudden arrhythmia death syndromes (SADS). It is a major cause of sudden, unexplained death in children and young adults, resulting in as many as 3,000–4,000 deaths per year in the United States. Its symptoms include seizures or fainting, often in response to stress.

LQTS was first described by C. Romano and coworkers in 1963 and by O. C. Ward in 1964, as a syndrome that was almost identical to Jervell and LangeNielsen syndrome, but without congenital deafness. Therefore, LQTS also is known as Romano-Ward syndrome or Ward-Romano syndrome.

LQTS involves irregularities in the recharging of the heart’s electrical system that occurs after each heartbeat or contraction. The QT interval is the period of relaxation or recovery that is required for the repolarization, or recharging, of the electrical system following each heart contraction. The depolarization that causes the heart to contract and the repolarization occur via the opening and closing of potassium, sodium, and calcium ion channels in the membranes of heart cells. As sodium channels in the heart open, positively charged sodium ions flow into

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K E Y T E R M S

Action potential—The wave-like change in the electrical properties of a cell membrane, resulting from the difference in electrical charge between the inside and outside of the membrane.

Arrhythmia—Abnormal heart rhythm, examples are a slow, fast, or irregular heart rate.

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

Beta-adrenergic blocker—A drug that works by controlling the nerve impulses along specific nerve pathways.

Depolarization—The dissipation of an electrical charge through a membrane.

Electrocardiogram (ECG, EKG)—A test used to measure electrical impulses coming from the heart in order to gain information about its structure or function.

Fibrillation—A rapid, irregular heartbeat.

Ion channel—Cell membrane proteins which control the movement of ions into and out of the cell. QT interval—The section on an electrocardiogram between the start of the QRS complex and the end of the T wave, representing the firing or depolarization of the ventricles and the period of recovery prior to repolarization or recharging for the next contraction.

Recessive—Genetic trait expressed only when present on both members of a pair of chromosomes, one inherited from each parent.

Repolarization—Period when the heart cells are at rest, preparing for the next wave of electrical current (depolarization).

Syncope—A brief loss of consciousness caused by insufficient blood flow to the brain. Tachycardia—An excessively rapid heartbeat; a heart rate above 100 beats per minute.

Torsade de pointes—A type of tachycardia of the ventricles that is characteristic of long-QT syndrome.

the cells, making the inner surfaces of the cell membranes more positive than the outside and creating the action potential, or electrical charge. During depolarization, the sodium channels shut and, after a delay, potassium channels open and allow positively charged potassium ions to move out of the cells, returning the cell

membranes to their resting state, in preparation for the next heart contraction.

Individuals with LQTS have an unusually long QT interval. If the electrical impulse for the next contraction arrives before the end of the QT recovery period, a specific arrhythmia arises in the ventricles, or lower chambers, of the heart. This arrhythmia is called polymorphous ventricular tachycardia, meaning fast heart (above 100 beats per second), or torsade de pointes, meaning turning of the points. A normal heartbeat begins in the right atrium of the heart and progresses down to the ventricles. In ventricular tachycardia, the heartbeat may originate in the ventricle. Usually this very fast and abnormal heartbeat reverts to normal. If it does not, it leads to ventricular fibrillation, in which the heart beats too fast, irregularly, and ineffectively. This can result in cardiac arrest and death. Variations in the QT interval from one heart cell to another also can cause arrhythmias and ventricular fibrillation in LQTS.

LQTS usually results from changes, or mutations, in one of six or more genes. These genes encode proteins that form the ion channels in the heart. Although such mutations can arise spontaneously in an individual, they are most often passed on from parent to offspring. Thus, LQTS usually runs in families.

Acquired LQTS is caused by factors other than genetic inheritance or mutation. Many different medications, including heart medicines, antibiotics, digestive medicines, psychiatric drugs, and anti-histamines, as well as certain poisons, can result in LQTS. Some of these drugs block potassium ion channels in the heart. Diuretic medications can cause LQTS by lowering levels of potassium, magnesium, and calcium in the blood. Mineral imbalances, resulting from chronic vomiting, diarrhea, or starvation, also can result in LQTS, as can strokes or other neurological problems or alcoholism. However, since only certain individuals develop LQTS under these circumstances, genetics also may play a role in the acquired disorder.

Genetic profile

Although all of the genes that are known to be involved in LQTS encode proteins that form sections or subunits of ion channels through cellular membranes, the type of LQTS depends on the specific gene defect.

Most forms of LQTS are autosomal dominant genetic disorders. Thus, the genes that cause LQTS are carried on one of the 22 pairs of autosomal chromosomes, rather than on the X or Y sex chromosomes. Furthermore, only one copy of the mutant gene is necessary for the development of LQTS. Thus, an individual

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who inherits a normal gene copy from one parent and an abnormal gene copy from the other parent is likely to have LQTS. The children of an individual with one normal gene copy and one mutated copy have a 50% chance of inheriting LQTS.

LQT1 and LQT5

LQT1 is the most common form of LQTS. It is caused by any of a number of gene mutations in the KVLQT1 (KvLQT1) gene located on the short arm of chromosome 11. KVLQT1 also is known as KCNQ1. This gene codes for an alpha-subunit of a voltage-gated potassium ion channel that is highly expressed in the heart. Protein subunits encoded by a mutant KVLQT1 gene may combine with protein subunits encoded by a normal KVLQT1 gene to form defective potassium channels. Although most mutations in KVLQT1 are dominant, some mutations in this gene may be recessive. In these cases, LQTS is present only in individuals with two abnormal KVLQT1 genes, one inherited from each parent.

The KCNE1 (MinK or IsK) gene on chromosome 21 codes for the beta or regulatory subunit that combines with the alpha-subunit encoded by KVLQT1. Together, they form the ion channel that is responsible for the cardiac IKs) potassium current. This is a slow ion channel that is activated by depolarization of the action potential of the heart, which causes the channel to open and potassium ions to move freely out of the cells during repolarization. Mutations in KCNE1 also can cause a defective potassium channel protein, resulting in the LQT1 form of LQTS. However, LQTS resulting from mutations in KCNE1 may be called LQT5.

Jervell and Lange-Nielsen syndrome is a very rare disorder in which an individual has two copies of an abnormal KVLQT1 or KCNE1 gene, one inherited from the mother and the other from the father. This syndrome is characterized by congenital deafness as well as a prolonged QT interval.

LQT2 and LQT6

LQT2 is the second most common form of LQTS. Mutations in the HERG gene (so-named because it is the human equivalent of a fruit fly gene called ether-a-go-go) can result in LQT2. HERG, located on chromosome 7, encodes a protein subunit of another potassium ion channel in the heart. Mutations in HERG result in loss of the potassium current called IKr.

The KCNE2 or MiRP1 (for MinK-related) gene is located next to MinK (KCNE1) on chromosome 21. It encodes a regulatory beta-subunit protein that combines with the protein encoded by HERG to form a potassium

ion channel. The form of LQTS resulting from mutations in the KCNE2 gene is known as LQT6.

Mutations in potassium channel genes reduce the number of functional potassium channels in the heart and lengthen the QT interval by delaying depolarization. Almost all cases of inherited LQTS result from mutations in KVLQT1 or KCNE1, causing LQT1, or mutations in HERG or KCNE2, causing LQT2.

LQT3

Mutations in the SCN5A gene can result in an uncommon form of LQTS known as LQT3. SCN5A, on chromosome 3, encodes a component of a cardiac sodium ion channel. Some mutations in this gene prevent the channel from being inactivated. Thus, although the channel opens normally and sodium ions flow into the cells with each contraction, the channel does not close properly. Sodium ions continue to leak into the cells, thereby prolonging the action potential. A different mutation in SCN5A decreases the flow of sodium ions into the cells, shortening the action potential and causing a distinct condition known as Brugada syndrome.

Other types of LQTS

Mutations in yet another gene, located on chromosome 4, can result in a type of LQTS known as LQT4.

A small number of individuals with LQTS have mutations in more than one of the known genes. Some families with inherited LQTS lack mutations in any of these known genes, suggesting the existence of other genes that can cause LQTS. Furthermore, individuals with identical LQTS genes may differ significantly in the severity of their symptoms, again suggesting the existence of other genes that can cause or modify LQTS.

Demographics

Large-scale studies of LQTS, such as the International Registry for LQTS established in 1979, have revealed that the disorder is much more prevalent than was believed originally. Inherited LQTS is estimated to occur in one out of every 5,000-10,000 individuals and it occurs in all racial and ethnic groups. LQTS may result in fetal death, may account for some cases of sudden infant death syndrome (SIDS), and has been implicated in many instances of sudden death and unexplained drownings among individuals who were previously without symptoms.

As an autosomal, non-sex-linked genetic disorder, LQTS should affect males and females in equal numbers. However, it appears to be more prevalent among women. Nearly 70% of the time, a female is the first member of a family to be recognized as having LQTS. Females are two

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TABLE 1

Drugs for patients with Long QT syndrome to avoid

	Drug name	Chemical name	General Use
ANESTHETICS/ASTHMA
Adrenaline		Epinephrine	Local anesthetics, or as an asthma medication
ANTIHISTAMINES
Seldane		Terfenadine	Allergies
Hismanal		Astemizole	Allergies
Benadryl		Diphenhydramine	Allergies
ANTIBIOTICS
E-Mycin, EES, EryPeds, PCE etc.		Erythromycin	Infections: lung, ear, throat
Bactrim, Septra		Trimethoprim & Sulfamethoxazole	Infections: urinary, ear, lung
Pentam intravenous		Pentamidine	Lung infections
HEART MEDICATIONS
Quinidine, Quinidex, Duraquin, Quiniqlute, etc.		Quinidine	Heart rhythm abnormalities
Pronestyl			Heart rhythm abnormalities
Norpace		Procainamide Disopyramide	Heart rhythm abnormalities
Betapace		Sotalol	Heart rhythm abnormalities
Lorelco		Probucol	High triglycerides, cholesterol
Vascor		Bepridil	Chest pain (angina)
GASTROINTESTINAL
Propulsid		Cisapride	For esophageal reflux, acid
ANTIFUNGAL DRUGS
Nizoral		Ketoconazole	Fungal infections
Diflucan		Fluconazole	Fungal infections
Sporanox		Itraconazole	Fungal infections
PSYCHOTROPIC DRUGS
Elavil, Norpramine, Viractil Compazine, Stelazine,		Amitriptyline (Tricyclics)	Depression
Thorazine Mellaril, Etrafon, Trilafon, others		Phenothiazine derivatives	Mental disorders
Haldol		Haloperidol	Mental disorders
Risperdal		Risperidone	Mental disorders
ORAP		Pimozide	Mental disorders
DIURETICS
Lozol		Indapamide	Water loss, edema
POTASSIUM LOSS
Many diuretics cause potassium loss and low levels
of potassium in the blood. Diarrhea and vomiting
may have similar results, all of which aggravate
symptoms of Long QT Syndrome.

to three times more likely than males to exhibit symptoms of LQTS. However, in general, males manifest symptoms of LQTS at an earlier age than females. At puberty, the QT interval shortens in males; whereas in females it stays the same or shortens only slightly. Therefore, unaffected women have slightly longer QT intervals than unaffected men. Men with LQT1 or LQT2 have shorter QT intervals than either women or children with these two forms of the disorder. Women also are more likely than men to develop drug-induced or acquired LQTS. These gender-related differences may be due to the effects of the female hormone estrogen on the regulation of cardiac ion channels, particularly potassium channels.

Signs and symptoms

Sudden death

Tragically for many individuals with LQTS, sudden death by cardiac arrest is the first symptom. For this reason, LQTS sometimes is referred to as a “silent killer.”

Approximately one-third of deaths from LQTS are not preceded by any symptoms of the disease. At least onethird of the individuals carrying a gene variant that causes LQTS do not exhibit any symptoms.

SIDS is the leading cause of death among infants between the ages of one month and one year. SIDS claims the lives of one or two out of every 1,000 infants. About 7,000 babies per year die of SIDS in the United States alone. In 1998, the results of a very large study, the Multicenter Italian Study of Neonatal Electrocardiography and SIDS, conducted under the direction of Peter J. Schwartz of the University of Milan, found that a large number of SIDS victims had prolonged QT intervals.

Syncope and seizures

Dizziness, sudden loss of consciousness or fainting spells (syncopes), or convulsive seizures are common symptoms of LQTS. These occur because the heart is

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unable to pump sufficient blood to the brain. Following a loss of consciousness or syncope, the torsade de pointes rhythm usually reverts spontaneously to a normal rhythm within one minute or less and the individual regains consciousness. These symptoms may appear first during infancy or early childhood, although sometimes no symptoms are evident until adulthood. Some individuals may experience syncopal episodes from childhood on; whereas others may experience one or two episodes as children, with no recurrence throughout adulthood. On average, males with LQTS first exhibit symptoms at about age eight and females at about age 14. These symptoms usually occur upon awakening, during strenuous physical activity, or during moments of excitement or stress.

Other symptoms

Newborn infants and children under the age of three with LQTS may exhibit slower than normal resting heart rates. Individuals with LQTS may experience irregular heartbeats accompanied by chest pain.

Gene-specific symptoms

Symptoms of LQTS vary depending on the specific gene mutation. Certain mutations in the KVLQT1 gene that cause LQT1 may result in arrhythmias when an individual is under stress. Exercise is a major trigger for cardiac events in LQT1. Swimming can trigger syncopic episodes and appears to be a gene-specific trigger in individuals with KVLQT1 mutations. Drowning is the second most common cause of accidental death in children and young adults and about 10% of such drownings are unexplained. Thus, LQT1 may account for many unexplained drownings and near-drownings.

Sudden loud noises, such as telephones or alarm clocks, are more likely to trigger arrhythmias and syncopic episodes in individuals with LQT2. Cardiac events, including syncope, aborted cardiac arrest, and sudden death, are more common among individuals with LQT1 or LQT2 than among those with LQT3. However, cardiac events are more likely to be lethal in individuals with LQT3. Certain variants of the SCN5A gene that cause LQT3 result in abnormal heart rhythms during sleep.

Individuals with some of the variants of the KCNE2 gene that cause LQT6 may be adversely affected by exercise and some medications.

Diagnosis

Electrocardiogram

A diagnosis of LQTS most often comes from an electrocardiogram (ECG or EKG). An ECG records the

		R		R
	P	T	P	T
Normal		Q S		Q S
		R		R
			T
Long QT	P			P
syndrome		Q S		Q S

A comparison of the “QT” interval found in a normal patient versus one diagnosed with long QT syndrome obtained from an electrocardiogram. The typical QT interval is 400440 miliseconds, but for patients with long QT syndrome the interval exceeds 460 milliseconds. This lengthened interval is obvious in the comparison above. (Gale Group)

electrical activity of the heart, using electrical leads placed at specific sites on the body. The electrical activity due to the depolarization and repolarization of the heart is recorded by each lead and added together. The recordings, on paper or on a monitor, show a series of peaks, valleys, and plateaus.

The QRS complex is a sharp peak and dip on the ECG that occurs as the electrical impulses fire the cells of the ventricles, causing contraction and depolarization of the action potential. The torsade de pointes, or turning of the points, refers to these spikes in the QRS complex. Sometimes it is possible to diagnose torsade de pointes from an ECG. The T wave on the ECG occurs as the cells recover and prepare to fire again with the next heartbeat. Thus, the T-wave represents the repolarization of the ventricles. The QT interval on the ECG is the period from the start of the depolarization of the ventricles (Q), as the electrical current traverses the ventricles from the inside to the outside, through the repolarization of the ventricles (T), as the current passes from the outside to the inside. Thus, the QT interval represents the firing and recovery cycle of the ventricles. In LQTS, the QT interval on the ECG may be a few one-hundredths of a second longer than normal. A QT interval that is longer than 440 milliseconds is considered to be prolonged. There also may be abnormalities in the T-wave of the ECG.

ECGs may vary depending on the specific mutation that is the cause of the LQTS. Furthermore, as many as 12% of individuals with LQTS may have normal-appear- ing or borderline-normal QT intervals on an ECG. An individual’s ECGs can vary, and additional ECGs or ECGs performed during exercise may reveal an abnormal QT interval. ECGs of parents or siblings also may con-

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tribute to a diagnosis, since one parent, and possibly siblings, may carry a gene variation that causes LQTS and, therefore, may exhibit a prolonged QT interval on an ECG.

Other diagnostic methods

Children with LQTS may exhibit a low heart rate; specifically, a resting heart rate that is below the second percentile for their age. A fast heart rate of 140-200 beats per minute may indicate tachycardia resulting from LQTS. Convulsive seizures due to LQTS sometimes are misdiagnosed as epilepsy, particularly in children.

Some individuF with LQTS may have low levels of potassium in their blood.

Genetic diagnosis

Some 200 specific changes have been found in the genes that are responsible for LQTS. Furthermore, as many as one-half of the individuals diagnosed with LQTS do not carry any of the known genetic variations. Thus, it can be difficult to diagnose LQTS on the basis of genetic testing. However, when family members are known to carry a specific LQTS gene mutation, genetic testing may be used to diagnose LQTS in other family members.

Treatment and management

Beta-blockers

Beta-adrenergic blockers, or beta-blockers, are the most common treatment for the ventricular arrythmia resulting from LQTS. Propranolol is the most frequently prescribed drug, although nadolol also is used. Propranolol lowers the heart rate and the strength of the heart muscle contractions, thereby reducing the oxygen requirement of the heart. Propranolol also regulates abnormal heart rates and reduces blood pressure.

Beta-blockers are very effective for treating LQT1, as well as many cases of LQT2. Thus, approximately 90% of individuals with LQTS can be treated successfully with these drugs. However, since the prophylactic effects disappear within one or two days of stopping the beta-blocker, treatment with these drugs usually lasts for life. Since the first symptom of LQTS may be sudden death, younger individuals with prolonged QT intervals or with family histories of LQTS commonly are treated with beta-blockers even in the absence of symptoms.

Beta-blockers such as propranolol are considered to be safe medications. Any side effects from propranolol are usually mild and disappear once the body has adjusted to the drug. However propranolol and other

beta-blockers can interact dangerously with many other medications.

Other drugs

As knowledge of the causes of LQTS increases, other drugs may prove to be more effective for treating some forms of LQTS. For example, mexiletine, a sodium-channel blocker, is used to shorten the QT interval in individuals with LQT3 that results from mutations in the SCN5A gene.

Potassium

Elevating the levels of blood potassium may relieve symptoms of LQTS in individuals with mutations in potassium channel genes. For example, increased blood potassium raises the outward potassium current in the HERG-encoded channel. Thus, treatment with potassium can compensate to some extent for the shortage of functional potassium ion channels in individuals with LQT2, thereby shortening the QT interval.

Surgical intervention

Left cardiac sympathetic denervation, the surgical cutting of a group of nerves connecting the brain and the heart, may reduce cardiac arrhythmias in individuals with LQTS. Pacemakers or automatic implanted cardioverter defibrillators (AICDs) also are used to regulate the heartbeat or to detect and correct abnormal heart rhythms. Sometimes, a pacemaker or AICD is used in combination with beta-blockers.

Preventative measures

Since the likelihood of developing symptoms of LQTS after about age 45 is quite low, individuals who are at least middle-aged when first diagnosed may not be treated. However, all individuals that have been diagnosed with LQTS must avoid reductions in blood potassium levels, such as those that occur with the use of diuretic drugs. Furthermore, individuals with LQTS must avoid a very long list of drugs and medications which can increase the QT interval or otherwise exacerbate the syndrome.

Infants in LQTS families should be screened with ECGs and monitored closely, due to the 41-fold increase in the risk of SIDS.

Individuals with LQTS usually are advised to refrain from competitive sports and to practice a “buddy” system during moderate exercise. Family members may be advised to learn cardiopulmonary resuscitation (CPR) in case of cardiac arrest.

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Prognosis

The prognosis usually is quite good for LQTS patients who receive treatment. Symptoms may disappear completely and, often, at least some of the ECG abnormalities revert to normal. In contrast, the death rate for LQTS can be very high among untreated individuals.

Pregnancy

Women with LQTS usually do not experience an increase in cardiac events during pregnancy or delivery. However, they may experience an increase in serious episodes in the months following delivery. This is especially true for women who have experienced syncopic episodes prior to pregnancy. This increase in symptoms may be due to the physical and emotional stress of the postpartum period. Women who receive beta-blocker therapy during pregnancy and following delivery experience far fewer cardiac events. Beta-blockers do not appear to adversely affect a pregnancy, nor do they appear to harm the fetus.

Resources

PERIODICALS

Ackerman, M.J., D.J. Tester, and C.J. Porter. “Swimming, a Gene-Specific Arrhythmogenic Trigger for Inherited Long QT Syndrome.” Mayo Clinic Proceedings 74 (November 1999): 1088–94.

Li, H., J. Fuentes-Garcia, and J.A. Towbin. “Current Concepts in Long QT Syndrome.” Pediatric Cardiology 21 (November 2000): 542–50.

Wang, Q., Q. Chen, and J.A. Towbin. “Genetics, Molecular Mechanisms and Management of Long QT Syndrome.” Annals of Medicine 30, no. 1 (February 1998): 58–65.

ORGANIZATIONS

Cardiac Arrhythmias Research and Education Foundation, Inc. 2082 Michelson Dr., #301, Irvine, CA 92612-1212. [phone] or [phone]. [e-mail]://www.longqt.org .

European Long QT Syndrome Information Center. Ronnerweg 2, Nidau, 2560 Switzerland 04(132) 331-5835. jmettler @bielnews.ch. http://www.bielnews.ch/cyberhouse/qt/qt

.html .

SADS Foundation. PO Box 58767, 508 East South Temple, Suite 20, Salt Lake City, UT 84102. [phone].http://www.sads.org .

WEBSITES

“Genetics of Long QT Syndrome/Cardiac Arrest.” DNA Sciences (2001). http://my.webmd.com/content/article/ 3204.676 .

“Heart of the Matter.” New Scientist (3 April 1999).http://www.newscientist.com/ns/19990403/newstory11

.html .

Lehmann, Michael. “Gender Differences in Long QT–What Are They?” Cardiac Arrhythmias Research and Education Foundation, Inc. http://www.longqt.com/lqts/genddif

.asp.htm .

Long QT Syndrome European Information Center.

http://www.qtsyndrome.ch/lqts.html .

Moss, Arthur J. “The Long QT Syndrome and Pregnancy.”

Cardiac Arrhythmias Research and Education Foundation, Inc. http://www.longqt.com/lqts/pregncy.asp

.htm .

“Study Links Abnormal Heart Rhythm to SIDS.” Mayo Foundation for Medical Education and Research. (16 August 2000). http://www.mayohealth.org/home?id HO00142 .

Vincent, G. Michael. An Overview of the Inherited Long QT Syndrome. (7 June 2000). http://www.sads.org .

Margaret Alic, PhD

Lou Gehrig disease see Amyotrophiclateral sclerosis

Lowe oculocerbrorenal syndrome see Lowe syndrome

I Lowe syndrome

Definition

Lowe syndrome is a rare genetic condition that affects males. It is caused by an enzyme deficiency. It affects many body systems including the eyes, the kidneys, and the brain.

Description

Lowe syndrome was first described by Dr. Charles Lowe in 1952. The syndrome is caused by a change (mutation) in the OCRL1 gene. This gene is responsible for the production of the enzyme phosphatidylinositol 4,5-bisphosphate 5-phosphatase. A mutation in the OCRL1 gene leads to a decrease in enzyme activity. This decrease in the activity of phosphatidylinositol 4,5-bis- phosphate 5-phosphatase is responsible for the physical and mental problems associated with Lowe syndrome. The reason why a deficiency of this enzyme causes Lowe syndrome is still unknown. Phosphatidylinositol 4,5-bis- phosphate 5-phosphate phosphatase is thought to be limited to a specific part of the cell called the “Golgi apparatus.” The relationship between the function of the Golgi apparatus, the enzyme deficiency, and the features of Lowe syndrome is unclear.

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Lowe syndrome

K E Y T E R M S

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

Cataract—A clouding of the eye lens or its surrounding membrane that obstructs the passage of light resulting in blurry vision. Surgery may be performed to remove the cataract.

Cerebro—Related to the head or brain.

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

Congenital—Refers to a disorder which is present at birth.

Germ line mosaicism—A rare event that occurs when one parent carries an altered gene mutation that affects his or her germ line cells (either the egg or sperm cells) but is not found in the somatic (body) cells.

Glaucoma—An increase in the fluid eye pressure, eventually leading to damage of the optic nerve and ongoing visual loss.

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.

Nystagmus—Involuntary, rhythmic movement of the eye.

Oculo—Related to the eye.

Renal—Related to the kidneys.

Rickets—A childhood disease caused by vitamin D deficiency, resulting in soft and malformed bones.

Strabismus—An improper muscle balance of the ocular musles resulting in crossed or divergent eyes.

Another name for Lowe syndrome is oculocerebrorenal syndrome of Lowe. This name describes the body systems most commonly affected by this genetic disease. The term “oculo” refers to the eye problems commonly seen in individuals with Lowe syndrome. Cataracts (cloudiness of the lens of the eye) are a classic feature and are usually present at birth (congenital). Other eye problems are also common. The term “cerebro” refers to the brain dysfunction commonly seen in Lowe syndrome. The majority of males with Lowe syndrome have mental retardation and behavior disturbances. The term “renal” represents the kidney problems associated with Lowe syndrome. The kidney problems can interfere with normal bone development and eventually lead to kidney failure.

Genetic profile

Changes (mutations) in the OCRL1 gene decrease the activity of the enzyme phosphatidylinositol 4,5-bis- phosphate 5-phosphatase. There have been many different mutations identified in the OCRL1 gene. These mutations may be different between families. The OCRL1 gene is located on the X chromosome. Since the OCRL1 gene is located on the X chromosome, Lowe syndrome is considered to be X-linked. This means that it only affects males.

A person’s sex is determined by his or her chromosomes. Males have one X chromosome and one Y chromosome, while females have two X chromosomes. Males who possess a mutation in their OCRL1 gene will develop Lowe syndrome. Females who possess a mutation in their OCRL1 gene will not; they are considered to be carriers. This is because females have another X chromosome without the mutation that allows normal function, and prevents them from getting this disease. If a woman is a carrier, she has a 50% risk with any pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk of having an affected son, and with every female pregnancy she has a 50% risk of having a daughter who is a carrier.

Demographics

Lowe syndrome affects approximately one in 100,000 live births. It occurs evenly among ethnic groups. Almost always, only male children are affected. Women carriers usually do not have physical or mental problems related to the disease.

Signs and symptoms

The signs and symptoms of Lowe syndrome are variable. Some individuals with Lowe syndrome have many

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Mental delays

Kidney failure

Tremor

Glaucoma

Kidney failure

Glaucoma

Muscle weakness

Mental delays

Rickets

Tremor

Cataracts

Mental delays

Rickets

Cataracts

(Gale Group)

severe symptoms, while other affected individuals have fewer, more mild symptoms.

Eye problems are a common feature of Lowe syndrome. Congenital cataracts are a classic feature of the disorder. These cataracts may be one of the first symptoms noticed during infancy. Approximately 50% of males with Lowe syndrome will develop increased pressure behind the eye (glaucoma). This pressure can damage the eye. Other eye problems include strabismus (crossed or divergent eyes), nystagmus (uncontrollable rhythmic eye movements), and microphthalmia (small eyes).

The nervous system (brain and nerves) is also typically affected by Lowe syndrome. Mental retardation is a common feature of Lowe syndrome. It can vary between mild and severe. Some males with Lowe syndrome have normal intelligence. Seizures and behavior disturbances can also be seen in individuals with Lowe syndrome. Behavior disturbances can include temper tantrums, aggression, obsessions, and repetitive hand movements. One of the first signs of brain dysfunction caused by Lowe syndrome is muscle weakness (hypotonia) during infancy.

Kidney problems are another common finding in individuals with Lowe syndrome. The kidneys normally filter chemicals and acids from the body. The kidneys allow the body to keep needed substances and to remove unneeded substances through the urine. Individuals with Lowe syndrome cannot do this properly, allowing needed substances (calcium, phosphate, etc.) to be excreted in the urine. This kidney disturbance can ultimately lead to kidney failure.

Individuals with Lowe syndrome frequently have slow growth and have short stature. Problems with bones can also develop due to the loss of certain substances through the kidneys. Rickets and easily breakable bones are common features. Joints may also become inflamed in individuals with Lowe syndrome.

Diagnosis

The diagnosis of Lowe syndrome is based initially on the presence of the symptoms of the disorder. Lowe syndrome is definitively diagnosed by measuring the activity of the enzyme phosphatidylinositol 4,5-bisphos- phate 5-phosphatase. When the activity of this enzyme is very low it is diagnostic of Lowe syndrome. In order to perform this test a small piece of skin must be removed from the patient’s body (skin biopsy). The enzyme is then measured from cells in this skin sample. In some cases it is also possible to look for a mutation in the OCRL1 gene. The presence of mutation confirms the diagnosis of Lowe syndrome in males.

Determining if a woman is a carrier of Lowe syndrome can be done several different ways. Females who carry a mutation in their OCRL1 gene commonly have changes in the lens of the eye. These changes can only be detected by an ophthalmologist with a special eye examination. These changes do not cause vision problems. The eye difference seen in carriers of Lowe syndrome is best observed once females reach adulthood. Recent reports suggest that a detailed eye exam can detect 90% of carriers. In addition to eye examinations, carrier detection can also be performed with DNA testing. If the OCRL1 muta-

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