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Copyright 2005, 2012
NORD is very grateful to M. Mahmood Hussain, MD, Professor, Department of Cell Biology and Pediatrics, SUNY Downstate Medical Center, for assistance in the preparation of this report.
Abetalipoproteinemia is a rare inherited disorder of/affecting fat metabolism. Abnormalities in fat metabolism result in malabsorption of dietary fat and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking, and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited as an autosomal recessive trait and is caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene.
Abetalipoproteinemia was first reported in the medical literature by doctors Bassen and Kornzweig in 1950 and is also known as Bassen-Kornzweig syndrome. The disorder is sometimes classified as a neuroacanthocytosis syndrome, which refers to a group of disorders characterized by acanthocytosis and neurological disorders, especially movement disorders.
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 intellectual disability has been reported.
In some cases, the damage or malfunction of the peripheral nervous system (peripheral neuropathy) may occur. The peripheral nervous system contains all of the nerves outside of the central nervous system. The associated symptoms can vary greatly from one person to another, but can include weakness of the muscles of the arms and legs or abnormal sensations such as tingling (paresthesias), burning or numbness.
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 may be due to vitamin A and/or E deficiency. If left untreated, visual acuity may deteriorate to virtual blindness by the fourth decade of life.
Less often, additional symptoms that affect the eyes have been reported including rapid, involuntary eye movements (nystagmus), droopy of the upper eyelid (ptosis), crossed eyes (strabismus), unequal size of the pupils (anisocoria), and weakness or paralysis of muscles that control eye movements (ophthalmoplegia).
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 blood cells (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.
In rare cases, fatty liver and scarring of the liver (cirrhosis) has also been reported.
Abetalipoproteinemia is caused by mutations in the MTTP gene. These mutations are inherited as an autosomal recessive trait. Genetic diseases are determined by two alleles, one received from the father and one from the mother. An allele refers to one of two or more alternate forms of a particular gene.
Recessive genetic disorders occur when an individual inherits two abnormal alleles for the same trait from each parent. If an individual receives one normal allele and one allele 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 the MTTP gene is 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.
The MTTP gene contains instructions for producing (encoding) a protein known as microsomal triglyceride transfer protein (MTTP or MTP). This protein is required for the proper assembly and secretion of apoB-containing lipoproteins in the liver and intestines. Mutations of the MTTP gene lead to low levels of functional MTP, which in turn, hinders the liver and intestines from making or secreting apoB-containing lipoproteins. The symptoms of abetalipoproteinemia are caused by the lack of apoB-containing lipoproteins in the plasma. Lipoproteins are substances that consist of fat (lipid) and protein molecules. They act as transporters that carry fats throughout the body. 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 absorb and transport fats throughout the body.
Recent research has also determined that MTP is also involved in the maturation of a family of proteins known as CD1, which are involved in lipid antigen-presentation to immune cells. More research is necessary to determine the complete functions of the MTTP protein and the exact underlying mechanisms that cause disease in abetalipoproteinemia.
Abetalipoproteinemia affects both males and females. There are no known racial or ethnic preferences for the disorder. Symptoms usually become apparent during infancy. The exact prevalence and incidence of abetalipoproteinemia is unknown, but it is estimated to affect less than 1 in 1,000,000 people in the general population.
Symptoms of the following disorders can be similar to those of abetalipoproteinemia. Comparisons may be useful for a differential diagnosis.
Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder that is highly variable in its expression. Severe cases are nearly indistinguishable from individuals with abetalipoproteinemia. Symptoms can include gastrointestinal symptoms such as steatorrhea, ataxia, retinitis pigmentosa, and neuropathy. Acanthocytosis occurs in some cases as well. Treatment of individuals with FHBL is similar to treatment for individuals with abetalipoproteinemia. FHBL is caused by mutations of the apoB gene and is inherited as an autosomal dominant trait.
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.)
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 arrhythmias). 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.)
A diagnosis of abetalipoproteinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including tests to measure lipid and apoB-containing lipoproteins in the plasma, determine the form and structure (morphology) of red blood cells and an eye (ophthalmological) exam.
Clinical Testing and Workup
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 or very low density lipoproteins, are not detectable in the plasma.
The identification of malformed red blood cells (acanthocytosis) may also be detected by blood tests.
Molecular genetic testing can confirm a diagnosis of abetalipoproteinemia by detecting a mutation of the MTP gene, but the test is only available on a clinical basis.
A complete neurological assessment, an eye examination and a liver (hepatic) ultrasound may be performed to evaluate the presence of potentially associated symptoms.
The treatment of abetalipoproteinemia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, liver specialists (hepatologists), eye specialists (ophthalmologists), specialists in the study of fats (lipidologists), gastroenterologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.
Most affected individuals 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 high doses of fat-soluble vitamins (e.g., A, E, K) helps to prevent or improve many of the symptoms associated with abetalipoproteinemia. For example, treatment with vitamin E supplementation (i.e. tocopherol therapy) may prevent the neurological and retinal complications associated with abetalipoproteinemia.
Additional treatment is symptomatic and supportive. Genetic counseling is recommended for families of children with abetalipoproteinemia.
Gene therapy is also been studied as another approach to treat individuals with abetalipoproteinemia. In gene therapy, a normal gene is introduced to produce the active protein and prevent the development and progression of the disease in question. However, at this time, there remain substantial technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
Contact for additional information about abetalipoproteinemia:
M. Mahmood Hussain, M.D.
Department of Cell Biology and Pediatrics
SUNY Downstate Medical Center
Brooklyn, NY 11203
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Report last updated: 2012/10/24 00:00:00 GMT+0