Lipidoses

Lipidoses are heredity disorders, passed from parents to their children, characterized by defects of the digestive system that impair the way the body uses fat from the diet. When the body is unable to properly digest fats, lipidsaccumulate in body tissues in abnormal amounts.

The digestion, storage, and use of fats from foods is a complex process thatinvolves hundreds of chemical reactions in the body. In most people, the bodyis already programmed by its genetic code to produce all of the enzymes andchemicals necessary to carry out these functions. These genetic instructionsare passed from parents to their offspring during reproduction.

People with lipidoses are born without the genetic codes needed to tell theirbodies how to complete a particular part of the fat digestion process. In most of these disorders, the body does not produce a certain enzyme or chemical. Over 30 different disorders of fat metabolism are related to genetic defects. Although the defects are passed from parents to children, the parents often do not have the disorders themselves.

The symptoms, available treatments, and long-term consequences of these conditions vary greatly. Some of the conditions become apparent shortly after theinfant is born; in others, symptoms may not develop until adulthood. For mostof the lipidoses, diagnosis is suspected based on the symptoms and family history. Blood tests, urine tests, and tissue tests can be used to confirm thediagnosis. Genetic testing can be used, in some cases, to identify the defective gene. Some of these disorders can be controlled with changes in the diet,medications, or enzyme supplements. For many, no treatment is available. Some may cause death in childhood or contribute to a shortened life expectancy.Some of the most common or most serious lipidoses are discussed below.

Approximately 1 in every 40,000 males is born with Fabry's disease. This condition has an X-linked, recessive pattern of inheritance, meaning that the defective gene is carried on the X chromosome. A female who carries a defectiverecessive gene on one of her two X chromosomes has a 50% chance of passing the defective gene to her sons who will develop the disorder associated with the defective gene (a male receives one X chromosome from his mother and one Ychromosome from his father). She also has a 50% chance of passing the defective recessive gene to her daughters who will be carries of the disorder (liketheir mother). Some female carries of Fabry's disease show mild signs of thedisorder, especially cloudiness of the cornea.

The gene that is defective in Fabry's disease causes a deficiency of the enzyme alpha-galactosidase A. Without this enzyme, fatty compounds starts to linethe blood vessels. The collection of fatty deposits eventually affects bloodvessels in the skin, heart, kidneys, and nervous system. The first symptomsin childhood are pain and discomfort in the hands and feet brought on by exercise, fever, stress, or changes in the weather. A raised rash of dark red-purple spots is common, especially on skin between the waistline and the knees.Other symptoms include a decreased ability to sweat and changes in the corneaor outer layer of the eye. Although the disease begins in childhood, it progresses very slowly. Kidney and heart problems develop in adulthood.

The diagnosis of Fabry's disease can be confirmed by a blood test to measurefor alpha-galactosidase A. Women who are carries of the defective gene can also be identified by a blood test.

Treatment of Fabry's disease focuses on prevention of symptoms and long-termcomplications. Daily doses of diphenylhydantoin (Dilantin) or carbamazapine (Tegretol) can prevent or reduce the severity of pain in the hands and feet associated with the condition. A low sodium, low protein diet may be beneficialto those patients who have some kidney complications. If kidney problems progress, kidney dialysis or kidney transplantation may be required. Enzyme replacement therapy is currently being explored.

Although patients with Fabry's disease usually survive to adulthood, they areat increased risk for stroke, heart attacks, and kidney damage.

Gaucher (pronounced go-shay) disease is the most common of the lipid storagedisorders. It is found in populations all over the world (20,00 to 40,000 people have a type of the disease), and it occurs with equal frequency in malesand females. Gaucher disease has a recessive pattern of inheritance, meaningthat a person must inherit a copy of the defective gene from both parents inorder to have the disease. The genetic defect causes a deficiency of the enzyme glucocerebrosidase that is responsible for breaking down a certain type offat and releasing it from fat cells. These fat cells begin to crowd out healthy cells in the liver, spleen, bones, and nervous system. Symptoms of Gaucher disease can start in infancy, childhood, or adulthood.

Three types of Gaucher disease have been identified, but there are many variations in how symptoms develop. Type 1 is the most common and affects both children and adults. It occurs much more often in people of Eastern European andRussian Jewish (Ashkenazi) ancestry, affecting one out of every 450 live births. The first signs of the disease include an enlarged liver and spleen, causing the abdomen to swell. Children with this condition may be shorter than normal. Other symptoms include tiredness, pain, bone deterioration, broken bones, anemia, and increased bruising. Type 2 Gaucher disease is more serious, beginning within the first few months after birth. Symptoms, which are similarto those in Type 1, progress rapidly, but also include nervous system damage. Symptoms of Type 3 Gaucher disease begin during early childhood with symptoms like Type 1. Unlike Type 2, the progress of the disease is slower, although it also includes nervous system damage.

Gaucher disease may be suspected based on symptoms and is confirmed with a blood test for levels of the enzyme. Samples of tissue from an affected area may also be used to confirm a diagnosis of the disease.

The symptoms of Gaucher disease can be stopped and even reversed by treatmentwith injections of enzyme replacements. Two enzyme drugs currently availableare alglucerase (Ceredase) and imiglucerase (Cerezyme). Other treatments address specific symptoms such as anemia, broken bones, or pain.

The pain and deformities associated with symptoms can make coping with this illness very challenging for individuals and families. With treatment and control of symptoms, people with Type 1 Gaucher disease may lead fairly long andnormal lives. Most infants with Type 2 die before the age of two. Children with Type 3 Gaucher disease may survive to adolescence and early adulthood.

Krabbe's disease is caused by a deficiency of the enzyme galactoside beta-galactosidase. It has a recessive pattern of inheritance and is believed to occur in one of 40,000 births in the United States. This condition, which is alsocalled globoid cell leukodystrophy or Krabbe leukodystrophy, is characterized by acute nervous system degeneration. It develops in early infancy with initial symptoms of irritability, vomiting and episodes of partial unconsciousness. Symptoms progress rapidly to seizures, difficulty swallowing, blindness,deafness, mental retardation, and paralysis. No treatment is available for Krabbe's disease, and children born with the disease die in infancy.

At least five different forms of Niemann-Pick disease (NPD) have been identified. The different types seem to be related to the activity level of the enzyme sphingomyelinase. In patients with Types A and B NPD, there is a build upof sphingomyelin in cells of the brain, liver, spleen, kidney and lung. TypeA is the most common form of NPD and the most serious, with death usually occurring by the age of 18 months. Symptoms develop within the first few monthsof life and include poor appetite, failure to grow, enlarged liver and spleen, and the appearance of cherry red spots in the retina of the eye. Type B develops in infancy or childhood with symptoms of mild liver or spleen enlargement and lung problems. Some adults with this form (Type E) may also show a loss of muscle coordination. Types C or D NPD are related to cholesterol transfer out of cells. Children with Types C or D grow normally in early childhood,but eventually develop difficulty in walking and loss of muscle coordination.Ultimately, the nervous system becomes severely damaged and these patients die. Type C occurs in any population, while Type D has been identified only inpatients from Nova Scotia, Canada.

Diagnosis is confirmed by analyzing a sample of tissue. Prenatal diagnosis ofTypes A and B of NPD can be done with amniocentesis or chorionic villus sampling.

Treatment consists of supportive care to deal with symptoms and the development of complications. Bone marrow transplantation is being investigated as a possible treatment. Low-cholesterol diets may be helpful for patients with Types C and D.

Patients with Type A NPD usually die within the first year and a half of life. Type B patients generally live to adulthood but suffer from significant liver and lung problems. With Types C and D NPD, there is significant nervous system damage leading to severe muscle spasms, seizures, and eventually, to coma and death. Some patients with Types C and D die in childhood, while less severely affected patients may survive to adulthood.

Refsum's disease has a recessive pattern of inheritance and affects populations from Northern Europe, particularly Scandinavians most frequently. It is due to a deficiency of phytanic acid hydroxylase, an enzyme that breaks down afatty acid called phytanic acid. This condition affects the nervous system, eyes, bones, and skin. Symptoms, which usually appear by age 20, include vision problems [retinitis pigmentosa and rhythmic eye movements (nystagmus)], loss of muscle coordination, loss of sense of smell (anosmia), pain, numbness, and elevated protein in the cerebrospinal fluid.

A diet free of phytanic acid (found in dairy products, tuna, cod, haddock, lamb, stewed beef, white bread, white rice, boiled potatoes, and egg yolk) canreduce some of the symptoms o. Plasmapheresis, a process where whole blood isremoved from the body, processed through a filtering system, and then returnto the body, may be used to filter phytanic acid from the blood.

Tay-Sachs disease (TSD) is a fatal condition caused by a deficiency of the enzyme hexosaminidase A (Hex-A). The defective gene that causes this disorder is found in roughly 1 in 250 people in the general population. However, certain populations have significantly higher rates of TSD. French-Canadians livingnear the St. Lawrence River and in the Cajun regions of Louisiana are at higher risk of having a child with TSD. The highest risk seems to be in people of Eastern European and Russian Jewish (Ashkenazi) descent. Tay-Sachs diseasehas a recessive pattern of inheritance, and approximately 1 in every 27 people of Jewish ancestry in the United States carries the TSD gene. Symptoms develop in infancy and are due to the accumulation of a fatty acid compound in the nervous system. Early symptoms include loss of vision and physical coordination, seizures, and mental retardation. Eventually, the child develops problems with breathing and swallowing. Blindness, paralysis, and death follow.

Carriers of the Tay-Sachs related gene can be identified with a blood test. Amniocentesis or chorionic villi sampling can be used to determine if the fetus has Tay-Sachs disease.

There is no treatment for Tay-Sachs disease. Parents who are identified as carriers may want to seek genetic counseling. If a fetus is identified as having TSD, parents may consider termination of the pregnancy.

Children born with Tay-Sachs disease become increasingly debilitated; most die by about age four.

Wolman's disease is caused by a genetic defect (with a recessive pattern of inheritance) that results in deficiency of an enzyme that breaks down cholesterol. This causes large amounts of fat to accumulate in body tissues. Symptomsbegin in the first few weeks of life and include an enlarged liver and spleen, adrenal calcification (hardening of adrenal tissue due to deposits of calcium salts), and fatty stools. No treatment is currently available for Wolman's disease, and death generally occurs before six months of age.

Couples who have family histories of genetic defects can undergo genetic testing and counseling to see if they are at risk for having a child with one ofthe lipidoses disorders. During pregnancy, cell samples can be collected fromthe fetus using amniocentesis or chorionic villi sampling. The results of these test can indicate if the developing fetus has a lipidosis disorder. Termination of the pregnancy may be considered in some cases.

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