Information on the following diseases can be found in the Related Disorders section of this report:

• Celiac Disease
• Hyperlipoproteinemia Type III
• Friedreich's Ataxia
• Ataxia with Vitamin E Deficiency

Individuals with abetalipoproteinemia may experience a wide variety of symptoms affecting various parts of the body including the gastrointestinal tract, neurological system, eyes, and blood.

Affected infants often present with symptoms relating to gastrointestinal disease, which occur secondary to poor fat absorption. Such symptoms include pale, bulky foul-smelling stools (steatorrhea), diarrhea, vomiting, and swelling (distension) of the abdomen. Affected infants often fail to gain weight and grow at the expected rate (failure to thrive). These symptoms result from the poor absorption of fat from the diet. In addition to poor fat absorption, fat-soluble vitamins such as vitamins A, E, and K are also poorly absorbed potentially resulting in vitamin deficiency.

Between the ages of 2 and 20 years, vitamin E deficiency may result in a variety of neurological complications that resemble spinocerebellar degeneration, a general term for a group of disorders characterized by progressive impairment of the ability to coordinate voluntary movements due to degeneration of certain structures in the brain (cerebellar ataxia). Ataxia results in a lack of coordination and, eventually, difficulty in controlling the range of voluntary movement (dysmetria). Additional neurological symptoms include loss of deep tendon reflexes such as at the kneecap, difficulty speaking (dysarthria), tremors, motor tics, and muscle weakness. Intelligence is usually normal, but developmental delays or mental retardation has been reported.

Some individuals with abetalipoproteinemia may develop skeletal abnormalities including backward curvature (lordosis) or backward and sideways curvature of the spine (kyphoscoliosis), a highly arched foot (pes cavus) or clubfoot. These skeletal abnormalities may result from muscle imbalances during crucial stages of bone development. Eventually, affected individuals may be unable to stand or to walk unaided due to progressive neurological and skeletal abnormalities.

In some cases affected individuals may develop a rare eye condition called retinitis pigmentosa in which progressive degeneration of the nerve-rich membrane lining the eyes (retina) results in tunnel vision, night blindness, and loss of peripheral vision. Affected individuals may eventually develop loss of visual acuity. Retinitis pigmentosa occurs most often around the age of 10 years and is due to vitamin A deficiency.

Individuals with abetalipoproteinemia may also have blood abnormalities including a condition called acanthocytosis in which malformed (i.e., burr-shaped) red blood cells (acanthocytes) are present in the body. Acanthocytosis may result in low levels of circulating red bloods (anemia). Anemia may result in tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, palpitations, headaches, and pale skin color. Additional blood abnormalities may be due to vitamin K deficiency. Blood clotting factor levels may be reduced resulting in bleeding tendencies such as severe gastrointestinal bleeding.

Abetalipoproteinemia is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Some individuals with abetalipoproteinemia have had parents who were blood relatives (consanguineous). All individuals carry some abnormal genes. Parents who are close relatives have a higher chance than unrelated parents of both carrying the same abnormal gene. This increases the risk of having children with a recessive genetic disorder.

Investigators have determined that abetalipoproteinemia may be caused by disruption or changes (mutations) of the microsomal triglyceride transfer protein (MTP) gene located on the long arm of (q) of chromosome 4 (4q22-q24).

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4q22-q24" refers to bands 22-24 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Symptoms of abetalipoproteinemia are caused by the lack of apoB-containing lipoproteins in the plasma, due to a defect in the ability of the liver and intestines to make or secrete apoB-containing lipoproteins. Lipoproteins are substances that consist of fat (lipid) and protein molecules. They act as transports that carry fats throughout the body. Microsomal triglyceride transfer protein is essential in creating lipoproteins. A deficiency in MTP results in a deficiency of lipoproteins such as very low density lipoproteins (VLDLs), low density lipoproteins (LDLs), and chylomicrons. This, in turn, results in the inability to properly transport and digest fats throughout the body.

Abetalipoproteinemia affects both males and females, although there is some indication that it affects males somewhat more often. Symptoms usually become apparent during infancy.

Symptoms of the following disorders can be similar to those of abetalipoproteinemia. Comparisons may be useful for a differential diagnosis:

Celiac disease is a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye, and barley. Consumption of gluten leads to abnormal changes of the mucous membrane (mucosa) of the small intestine, impairing its ability to properly absorb fats and additional nutrients during digestion (intestinal malabsorption). Symptom onset may occur during childhood or adulthood. In affected children, such symptoms may include diarrhea, vomiting, weight loss or lack of weight gain, painful abdominal bloating, irritability, and/or other abnormalities. Affected adults may have diarrhea or constipation; abdominal cramping and bloating; abnormally bulky, pale, frothy stools that contain increased levels of fat (steatorrhea); weight loss; anemia; muscle cramping; bone pain; exhaustion (lassitude); and/or other symptoms and findings. Although the exact cause of celiac disease is unknown, genetic, immunologic, and environmental factors are thought to play some role. (For more information on this disorder, choose "Celiac" as your search term in the Rare Disease Database.)

Hyperlipoproteinemia type III, also known as dysbetalipoproteinemia or broad beta disease, is a rare genetic disorder characterized by improper breakdown (metabolism) of certain fatty materials known as lipids, specifically cholesterol and triglycerides. This results in the abnormal accumulation of lipids in the body (hyperlipidemia). Affected individuals may develop multiple yellowish, lipid-filled bumps (papules) or plaques on the skin (xanthomas). Affected individuals may also develop a buildup of fatty materials in the blood vessels (artherosclerosis) potentially obstructing blood flow and resulting in coronary heart disease or peripheral vascular disease. Most cases of hyperlipoproteinemia type III are inherited as an autosomal recessive trait. (For more information on this disorder, choose "hypolipoproteinemia type III" as your search term in the Rare Disease Database.)

Friedreich's ataxia is a genetic, progressive, neurologic movement disorder that typically becomes apparent before adolescence. Initial symptoms may include unsteady posture, frequent falling, and progressive difficulties walking due to an impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; increasing incoordination of the arms and hands; slurred speech (dysarthria); and rapid, involuntary eye movements (nystagmus). Friedreich's ataxia may also be associated with cardiomyopathy, a disease of cardiac muscle that may be characterized by shortness of breath upon exertion (dyspnea), chest pain, and irregularities in heart rhythm (cardiac arrythmias). Some affected individuals may also develop diabetes mellitus, a condition in which there is insufficient secretion of the hormone insulin. Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite, fatigue, and blurred vision. Friedreich's ataxia may be inherited as an autosomal recessive trait. Cases in which a family history of the disease has not been found may represent new genetic changes (mutations) that occur spontaneously (sporadically). (For more information on this disorder, choose "Friedreich's Ataxia" as your search term in the Rare Disease Database.)

Ataxia with vitamin E deficiency (AVED) is a rare inherited neurodegenerative disorder characterized by impaired ability to coordinate voluntary movements (ataxia) and disease of the peripheral nervous system (peripheral neuropathy). AVED is a progressive disorder that can affect many different systems of the body (multisystem disorder). Specific symptoms vary from case to case. In addition to neurological symptoms, affected individuals may experience eye abnormalities, disorders affecting the heart muscles (cardiomyopathy), and abnormal curvature of the spine (scoliosis). AVED is extremely similar to a more common disorder known as Friedreich's ataxia. AVED is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Ataxia with Vitamin E Deficiency" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of abetalipoproteinemia is made based upon a thorough clinical evaluation and a variety of specialized tests. Blood tests will detect low levels of both lipids, such as cholesterol and triglycerides, and lipid-soluble vitamins, such as A, E, and K. ApoB-containing lipoproteins, such as chylomicrons, are not detectable in the plasma. The identification of malformed red blood cells (acanthocytosis) may also be detected by blood tests. Genetic testing may reveal mutations of the MTP gene.

Treatment
Most individuals with abetalipoproteinemia respond to dietary therapy that consists of a diet that is low in fat especially long-chain saturated fatty acids. The reduction of the intake of dietary fats generally relieves gastrointestinal symptoms. The administration of fat-soluble vitamins (e.g., A, E, K) is important in preventing or improving many of the symptoms associated with abetalipoproteinemia.

Additional treatment is symptomatic and supportive. Genetic counseling is recommended for families of children with abetalipoproteinemia.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOK
Iqbal J, Yakubov R, Mahmood Hussain M, Med L. Abetalipoproteinemia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:358.

JOURNAL ARTICLES
Stevenson VL, Hardie RJ. Acanthocytosis and neurological disorders. J Neurol. 2001;248:87-94.

Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of microsomal triglyceride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000;20:663-97.

Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M. Microsomal triglyceride transfer protein and abetalipoproteinemia. Ann Endocrinol (Paris). 2000;61:125-9.

Ohashi K, Ishibashi S, Osuga J, et al., Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia. J Lipid Research. 2000;41:1199-1204.

Narcisi TM, Shoulders CC, Chester SA, et al., Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am J Hum Genet. 1995;57:1298-310.

Rader DJ, Brewer HB Jr., Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. JAMA. 1993;270:865-9.

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:200100; Last Update:11/13/1998. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=200100 Accessed on: 2/12/2005.

Shafer FE. Acanthocytosis. eMedicine Journal. 2002;3:11pp. Available at: http://www.emedicine.com/ped/topic2.htm Accessed On: 2/12/2005