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

Limb-girdle muscular dystrophy

dystrophy muscular girdle-Limb

Limb-girdle muscular dystrophy

used. A wheelchair or scooter can help when walking becomes difficult. Medications are often prescribed for cardiomyopathies and heart conduction defects. A device such as a pacemaker that creates normal contractions of the heart muscle may be necessary for some people with heart muscle abnormalities.

Gene therapy may one day cure LGMD. Gene therapy introduces unchanged copies of a LGMD gene into the muscle cells. The goal of therapy is for the normal LGMD gene to produce normal protein that will allow the muscle cells to function normally. As of 2001 gene therapy clinical trials have been temporarily halted but they are likely to continue in the near future. It will take quite a few years, however, for gene therapy to become a viable way to treat LGMD.

Prognosis

The prognosis of LGMD varies tremendously. Most people with LGMD, however do not have severe symptoms and most experience a normal lifespan. Cardiac and respiratory difficulties can, however, decrease the lifespan.

Resources

PERIODICALS

Bushby K. “The limb-girdle muscular dystrophies—multiple genes, multiple mechanisms.” Human Molecular Genetics 8 (1999): 1875–1882.

Bushby K. “Making sense of the limb-girdle muscular dystrophies.” Brain 122 (1999): 1403–1420.

Sunada, Yoshide. “The Muscular Dystrophies.” Contemp Neurol Ser 57, no. 5 (2000): 77–103.

Zatz, M., M. Vainzof, and M.R. Passos-Bueno. “Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes.” Current Opinion in Neurology 13, no. 5 (October 2000): 511–517.

ORGANIZATIONS

Muscular Dystrophy Association—Canada. 2345 Yonge St., Suite 900, Toronto, ONT M4P 2E5. Canada (416) 4882699. info@mdac.ca. http://www.mdac.ca/main.html .

Muscular Dystrophy Association. 3300 East Sunrise Dr., Tucson, AZ 85718. (520) 529-2000 or (800) 572-1717.http://www.mdausa.org .

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

WEBSITES

Hoffman, Eric, Cheryl Scacheri, and Elena Pegoraro. “LimbGirdle Muscular Dystrophy Overview.” Gene Clinicshttp://www.geneclinics.org/profiles/lgmd-overview/ index.html . (2 February 2001).

Lisa Maria Andres, MS, CGC

Lipoprotien-lipase deficency see

Hyperlipoproteinemia Type I

I Lissencephaly

Definition

Lissencephaly, literally meaning smooth brain, is a rare birth abnormality of the brain that results in profound mental retardation and severe seizures.

Lissencephaly is caused by an arrest in development of the fetal brain during early pregnancy. The cerebral cortex, the top layer of the brain controlling higher thought processes, does not develop the normal sulci, the indentations or valleys in the cortex, and gyri, the ridges or convolutions seen on the surface of the cortex. Instead, the cortex in a person with lissencephaly is thickened and smooth with disorganized neurons that have not migrated to their proper places. The typical cortex has six layers of neurons, but brains with lissencephaly usually have only four.

Description

The condition was first reported in 1914 by pathologists Culp and Erhardt, who described a human brain with a smooth surface, lacking the normal gyri. They called it lissencephaly.

Lissencephaly is one of a number of conditions called “neural migration disorders” that occur because the developing neurons do not proceed correctly to their normal place in the brain’s cortex during fetal development. In fact, the brain of a person with lissencephaly, with its smooth and immature cortex, resembles a typical human fetal brain at about 10 to 14 weeks of development.

Children with lissencephaly are almost always severely to profoundly mentally retarded, and the vast majority develop seizures that are difficult to treat. Life expectancy is reduced, and survivors need constant care.

Lissencephaly can occur as an isolated birth abnormality or can be one of many birth abnormalities occurring together in a specific inherited syndrome. There are at least 10 inherited syndromes that include lissencephaly and many more that include variants of this brain malformation. Lissencephaly can also occur by itself without other characteristics.

Some cases of lissencephaly are caused by new changes in the genetic material of that particular baby— these cases are caused by sporadic, or random, gene

Lissencephaly

Lissencephaly

K E Y T E R M S

Agyria—The absence of gyri, or convolutions, in the cerebral cortex.

Cerebellum—A portion of the brain consisting of two cerebellar hemispheres connected by a narrow vermis. The cerebellum is involved in control of skeletal muscles and plays an important role in the coordination of voluntary muscle movement. It interrelates with other areas of the brain to facilitate a variety of movements, including maintaining proper posture and balance, walking, running, and fine motor skills, such as writing, dressing, and eating.

Cerebral cortex—The outer surface of the cerebrum made up of gray matter and involved in higher thought processes.

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

Heterotopia—Small nodules of gray matter that are present outside the cortex.

Lissencephaly—A condition in which the brain has a smooth appearance because the normal convolutions (gyri) failed to develop.

Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain.

Microcephaly—An abnormally small head.

Pachygyria—The presence of a few broad gyri (folds) and shallow sulci (grooves) in the cerebral cortex.

Prenatal diagnosis—The determination of whether a fetus possesses a disease or disorder while it is still in the womb.

Subcortical band heterotopia—A mild form of lissencephaly type 1 in which abnormal bands of gray and white matter are present beneath the cortex near the ventricles.

Ventricle—The fluid filled spaces in the center of the brain that hold cerebral spinal fluid.

mutations (also called de novo). This means that the genetic change is not present in the parents or anyone else in the family. Some cases of lissencephaly are caused by rearrangements of chromosome material that can be inherited from a healthy parent. Other types of

lissencephaly are inherited in an autosomal recessive pattern. This means that a couple who has a child with an autosomal recessive lissencephaly syndrome has a 25% chance in any future pregnancy to have another affected child. There are also types of lissencephaly caused by changes in a gene or genes on the X chromosome. X- linked lissencephaly affects mainly males, who have only one X chromosome. Females who carry an X-linked gene change on one of their two X chromosomes often have mild brain changes.

Other known causes of lissencephaly include viral infections of the fetus or insufficient blood supply to the brain during the first trimester of pregnancy.

Genetic profile

There are a number of subtypes of lissencephaly that are distinguished by differences in the physical structure of the brain. “Classical,” or type 1, lissencephaly and cobblestone dysplasia, or type 2, lissencephaly are the most common subtypes.

Classical, or type 1, lissencephaly consists of a brain surface that is completely smooth except for a few shallow valleys (sulci). The cortex is thicker than normal and there are clumps of neurons found in areas outside the cortex (heterotopia). The corpus callosum, the band of tissue between the hemispheres of the brain, is often small and is sometimes absent. The posterior ventricles, the fluid-filled spaces in the center of the brain, are often larger than normal.

Type 1 lissencephaly can be seen in a number of genetic syndromes and can also occur by itself in a condition called Isolated Lissencephaly Sequence (ILS). The vast majority of cases of ILS is a result of mutations or deletions (missing sections) in one of two different genes involved in brain development.

The gene causing the majority of cases of ILS is called the LIS1 and is located on the short arm of chromosome 17. Between 40% and 64% of persons with ILS have a deletion of a portion of the LIS1 gene, and about 24% have a mutation that disrupts the normal function of the gene. Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members.

Another 12% of persons with ILS have a mutation in a gene called XLIS (or DCX), located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males and may or may not cause symptoms in the mothers who carry the mutation.

There are also a few cases of ILS that appear to be inherited in an autosomal recessive pattern. As of 2001, the mutated genes for this and other types of ILS have not been discovered.

Lissencephaly

Lissencephaly

Individuals with subcortical band heterotopia (SBH), a milder form of lissencephaly often seen in female carriers of XLIS, often have minor changes in the gyri, shallow sulci, and ribbons of white and gray matter beneath the cortex that show up on MRIs.

MRI findings in type 2 lissencephaly can include a cobblestone appearance of the cortex, enlarged ventricles, abnormalities of the white matter, and changes in the cerebellum, corpus callosum and brain stem.

A CT scan can be done to look for calcium deposits in the midline of the brain. Calcium deposits are common in MDS but not found in other lissencephaly syndromes.

In addition to MRI and CT testing, a careful clinical evaluation and examination by a medical geneticist is necessary to confirm the diagnosis and evaluate the child for the presence of a syndrome. It is essential for a child to have a precise diagnosis in order for genetic counselors to be able to give the family complete and accurate information about the inheritance pattern and chances for the condition to recur in future children.

To confirm the diagnosis of MDS or ILS, chromosome testing and other specialized genetic tests are often helpful. A test called fluorescence in situ hybridization (FISH) is used to detect LIS1 gene deletions. High resolution chromosome testing can often determine whether a deletion is sporadic or due to an inherited chromosome rearrangement. If necessary, mutation analysis, looking for specific errors in the sequence of the LIS1 or XLIS gene, can be performed.

Parents of a child with ILS who has a confirmed deletion or mutation in LIS1, and who have normal genetic studies themselves, have a less than 1% chance of having another child with ILS. Similarly, MDS with a confirmed sporadic deletion in LIS1 has a low chance of recurring. MDS caused by a chromosome rearrangement carries a higher chance of happening again. Actual risks depend on the specific rearrangement.

XLIS mutations are often inherited from a carrier mother. If a woman has genetic testing and is confirmed to have an XLIS mutation, she will have a 25% chance with each pregnancy to have an affected male and a 25% chance to have a carrier female who may have SBH.

If a detectable mutation, deletion, or chromosome rearrangement has been confirmed in the affected family member, prenatal diagnosis is available during future pregnancies. Ultrasound of the fetal anatomy during pregnancy cannot diagnose lissencephaly. However, ultrasound performed by a specialist at 18 to 22 weeks of pregnancy can sometimes detect other birth abnormalities that occur in some of the syndromes involving lissencephaly.

Treatment and management

There is no treatment or cure for lissencephaly. Seizures occur in almost all children with lissencephaly and are often difficult to control, even with the strongest anti-seizure medications. A severe type of seizure called infantile spasms can occur and may need to be treated with injections of adrenocorticotropic hormone (ACTH), although this treatment is not always effective.

Feeding difficulties can include choking, gagging, or regurgitating food or liquid. Aspiration, swallowing food down the trachea and into the lungs, is a serious problem that can lead to pneumonia. Liquids and thin foods can be thickened to make swallowing easier. There are medications available to help with reflux. Children who continue to have serious problems may need a permanent feeding tube placed into the stomach to ensure adequate nutrition.

Physical and occupational therapy can help prevent or reduce tightening of the joints and help to normalize muscle tone. However, the improvements are often limited and temporary.

Prognosis

Persons with classical lissencephaly usually need lifelong care for all basic needs. Many babies will not live past infancy, but the average age of survival depends on the particular syndrome involved, the type of lissencephaly, and the severity of the brain abnormalities in a given child. Babies with MDS usually die by two years of age, but the majority of persons with ILS live into childhood, although often not into adulthood. Many babies with cobblestone dysplasia die in infancy; however, some affected people have lived into their 20s. In contrast, persons with SBH have very variable signs and symptoms, may be asymptomatic, mildly affected or severely retarded, and may have near-normal or normal lifespans.

Resources

PERIODICALS

Berg, M.J., et al. “X-linked Female Band Heterotopia-Male Lissencephaly Syndrome.” Neurology 50 (1998): 11431146.

Dobyns, W.B., et al. “Differences in the Gyral Pattern Distinguish Chromosome 17-linked and X-linked Lissencephaly.” Neurology 53 (1999): 270-277.

Dobyns, W.B., et al. “Lissencephaly and Other Malformation Syndromes of Cortical Development: 1995 Update.” Neuropediatrics 26 (1995): 132-147.

Matsumoto, N., et al., “Mutation Analysis of the DCX Gene and Genotype/Phenotype Correlation in Subcortical Band Heterotopia.” European Journal of Human Genetics 9 (Jan 2001): 5-12.

ORGANIZATIONS

American Epilepsy Society. 342 North Main St., West Hartford, CT 06117. (860) 586-7505. Fax: (860 586-7550. info@aesnet.org. http://www.aesnet.org .

Epilepsy Foundation of America. 4351 Garden City Dr., Suite 406, Landover, MD 20785-2267. (301) 459-3700 or (800) 332-1000. http://www.epilepsyfoundation.org .

Lissencephaly Network, Inc. 716 Autumn Ridge Lane, Fort Wayne, IN 46804-6402. (219) 432-4310. Fax: (219) 4324310. lissennet@lissencephaly.org. http://www

.lissencephaly.org .

WEBSITES

Dobyns, William B. [1999]. “Lissencephaly Overview.”

GeneClinics: Lissencephaly Overview. University of Washington, Seattle. http://www.geneclinics.org/ profiles/lis-overview/ .

NINDS Lissencephaly Information Page. http://www.ninds

.nih.gov/health_and_medical/disorders/lissencephaly

.htm?format printable .

Lissencephaly Contact Group (UK).

http://www.lissencephaly.org.uk/index.htm .

The Lissencephaly Research Project (University of Chicago) http://www.genes.uchicago.edu/ucgs/lissproj.html

Barbara J. Pettersen

I Liver cancer

Definition

Liver cancer is a form of cancer with a high mortality rate. Liver cancers can be classified into two types. They are either primary, when the cancer starts in the liver itself; or metastatic, when the cancer has spread to the liver from some other part of the body.

Description

Primary liver cancer

Primary liver cancer is a relatively rare disease in the United States, representing about 2% of all malignancies. It is, however, much more common in other parts of the world, representing from 10–50% of malignancies in Africa and parts of Asia. The American Cancer Society estimates that in the United States in 2001, at least 16,200 new cases of liver cancer will be diagnosed (10,700 in men and 5,500 in women), causing roughly 14,100 deaths.

In adults, most primary liver cancers belong to one of two types: hepatomas, or hepatocellular carcinomas, which start in the liver tissue itself; and cholangiomas, or

cholangiocarcinomas, which are cancers that develop in the bile ducts inside the liver. About 75% of primary liver cancers are hepatomas. In the United States, about five persons in every 200,000 will develop a hepatoma; in Africa and Asia, over 40 persons in 200,000 will develop this form of cancer. Two rare types of primary liver cancer are mixed-cell tumors, or undifferentiated tumors.

There is one type of primary liver cancer that usually occurs in children younger than four years of age and between the ages of 12–15. This type of childhood liver cancer is called a hepatoblastoma. Unlike liver cancers in adults, hepatoblastomas have a good chance of being treated successfully. Approximately 70% of children with hepatoblastomas experience complete cures. If the tumor is detected early, the survival rate is over 90%.

Metastatic liver cancer

The second major category of liver cancer, metastatic liver cancer, is about 20 times as common in the United States as primary liver cancer. Because blood from all parts of the body must pass through the liver for filtration, cancer cells from other organs and tissues easily reach the liver, where they can lodge and grow into secondary tumors. Primary cancers in the colon, stomach, pancreas, rectum, esophagus, breast, lung, or skin are the most likely to spread (metastasize) to the liver. It is not unusual for the metastatic cancer in the liver to be the first noticeable sign of a cancer that started in another organ. After cirrhosis, metastatic liver cancer is the most common cause of fatal liver disease.

Genetic profile

Hepatocellular carcinoma has occasionally been reported to occur in familial clusters. It appears that firstdegree relatives (siblings, children, or parents) of people with primary liver cancer are 2.4 times more likely to develop liver cancer themselves. This finding indicates a small overall genetic component, however, specific disease genes have not yet been identified. Certain genetic diseases are associated with a higher risk for liver cancers. These include Hemochromatosis, alpha-1 Antitrypsin deficiency, glycogen storage disease, tyrosinemia, Fanconi anemia, and Wilson disease.

Demographics

Hepatocellular carcinoma is the sixth most common cancer of men and eleventh most common cancer of women worldwide, affecting 250,000 to one million individuals annually. Liver cancer is becoming more common in the United States. It is 10 times more common in

cancer Liver

Liver cancer

K E Y T E R M S

Aflatoxin—A substance produced by molds that grow on rice and peanuts. Exposure to aflatoxin is thought to explain the high rates of primary liver cancer in Africa and parts of Asia.

Alpha-fetoprotein (AFP)—A chemical substance produced by the fetus and found in the fetal circulation. AFP is also found in abnormally high concentrations in most patients with primary liver cancer.

Cirrhosis—A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.

Hepatitis—A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.

Metastatic cancer—A cancer that has spread to an organ or tissue from a primary cancer located elsewhere in the body.

Africa and Asia where liver cancer is the most common type of cancer. Liver cancer affects men more often than women and, like most cancers, it is more common in older individuals.

Risk factors for primary liver cancer

The exact cause of primary liver cancer is still unknown. In adults, however, certain factors are known to place some individuals at higher risk of developing liver cancer. These factors include:

•Exposure to hepatitis B (HBV) or hepatitis C (HBC) viruses. In Africa and most of Asia, exposure to hepatitis B is an important factor; in Japan and some Western countries, exposure to hepatitis C is connected with a higher risk of developing liver cancer. In the United States, nearly 25% of patients with liver cancer show evidence of HBV infection. Hepatitis is commonly found among intravenous drug abusers.

•Exposure to substances in the environment that tend to cause cancer (carcinogens). These include a substance produced by a mold that grows on rice and peanuts (aflatoxin); thorium dioxide, which was used at one time as a contrast dye for x rays of the liver; and vinyl chloride, a now strictly regulated chemical used in manufacturing plastics.

•Cirrhosis. Hepatomas appear to be a frequent complication of cirrhosis of the liver. Between 30 and 70% of hepatoma patients also have cirrhosis. It is estimated that a patient with cirrhosis has 40 times the chance of developing a hepatoma than a person with a healthy liver.

•Use of oral estrogens for birth control. This association is based on studies of older, stronger birth control pills that are no longer prescribed. It is not clear if newer, lower dose birth control pills increase risk for liver cancer.

•Use of anabolic steroids (male hormones) for medical reasons or strength enhancement. Cortisone-like steroids do not appear to increase risk for liver cancer.

•Hereditary hemochromatosis. Hemochromatosis is a disorder characterized by abnormally high levels of iron storage in the body. It often develops into cirrhosis.

•Geographic location. Liver cancer is 10 times more common in Asia and Africa than in the United States.

•Male sex. The male/female ratio for hepatoma is 4:1.

•Age over 60 years.

Signs and symptoms

The early symptoms of primary, as well as metastatic, liver cancer are often vague and not unique to liver disorders. The long lag time between the beginning of the tumor’s growth and signs of illness is the major reason why the disease has such a high mortality rate. At the time of diagnosis, patients are often tired, with fever, abdominal pain, and loss of appetite. They may look emaciated and generally ill. As the tumor grows bigger, it stretches the membrane surrounding the liver (the capsule), causing pain in the upper abdomen on the right side. The pain may extend into the back and shoulder. Some patients develop a collection of fluid, known as ascites, in the abdominal cavity. Others may show signs of bleeding into the digestive tract. In addition, the tumor may block the ducts of the liver or the gall bladder, leading to jaundice. In patients with jaundice, the whites of the eyes and the skin may turn yellow, and the urine becomes dark-colored.

Diagnosis

Physical examination

If the doctor suspects a diagnosis of liver cancer, he or she will check the patient’s history for risk factors and pay close attention to the condition of the patient’s abdomen during the physical examination. Masses or lumps in the liver and ascites can often be felt while the

patient is lying flat on the examination table. The liver is usually swollen and hard in patients with liver cancer; it may be sore when the doctor presses on it. In some cases, the patient’s spleen is also enlarged. The doctor may be able to hear an abnormal sound (bruit) or rubbing noise (friction rub) if he or she uses a stethoscope to listen to the blood vessels that lie near the liver. The noises are caused by the pressure of the tumor on the blood vessels.

Laboratory tests

Blood tests may be used to test liver function or to evaluate risk factors in the patient’s history. Between 50% and 75% of primary liver cancer patients have abnormally high blood serum levels of a particular protein (alpha-fetoprotein or AFP). The AFP test, however, cannot be used by itself to confirm a diagnosis of liver cancer, because cirrhosis or chronic hepatitis can also produce high alpha-fetoprotein levels. Tests for alkaline phosphatase, bilirubin, lactic dehydrogenase, and other chemicals indicate that the liver is not functioning normally. About 75% of patients with liver cancer show evidence of hepatitis infection. Again, however, abnormal liver function test results are not specific for liver cancer.

Imaging studies

Imaging studies are useful in locating specific areas of abnormal tissue in the liver. Liver tumors as small as an inch across can now be detected by ultrasound or computed tomography scan (CT scan). Imaging studies, however, cannot tell the difference between a hepatoma and other abnormal masses or lumps of tissue (nodules) in the liver. A sample of liver tissue for biopsy is needed to make the definitive diagnosis of a primary liver cancer. CT or ultrasound can be used to guide the doctor in selecting the best location for obtaining the biopsy sample. Chest x rays may be used to see whether the liver tumor is primary or has metastasized from a primary tumor in the lungs.

Liver biopsy

Liver biopsy is considered to provide the definite diagnosis of liver cancer. In about 70% of cases, the biopsy is positive for cancer. In most cases, there is little risk to the patient from the biopsy procedure. In about 0.4% of cases, however, the patient develops a fatal hemorrhage from the biopsy because some tumors are supplied with a large number of blood vessels and bleed very easily.