Abetalipoproteinemia is a rare inherited disorder affecting fat absorption by the intestine and mobilization by the liver. Inability to absorb fat results in deficiencies of lipids 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 spiky or burr-shaped red blood cells (acanthocytosis) and neurological disorders, especially movement disorders.
Signs & Symptoms
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 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 fat-soluble vitamin deficiency. Further, patients do not have any apoB-containing lipoproteins in their plasma, and consequently they have very low levels of triglycerides, cholesterol and phospholipids. Thus, lipids and fat soluble vitamins are inadequately transported throughout the blood stream. Some patients may also have reduced non-apoB-containing lipoproteins (high density lipoproteins) or apoA1 levels in their plasma.
Between the ages of 2 and 20 years, a variety of neurological complications occur 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 people, 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.
Some 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, loss of color 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 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 deformed (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.
Patients may have fatty liver, which can cause liver damage. In rare cases, fibrosis or scarring of the liver (cirrhosis) has also been reported.
Abetalipoproteinemia is caused by mutations in the MTTP gene and is inherited as an autosomal recessive genetic condition. 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 altered 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%.
All individuals carry some abnormal genes. Parents who are close relatives have a higher chance than unrelated parents of both carrying the same altered gene. Some individuals with abetalipoproteinemia have had parents who were blood relatives (consanguineous). This increases the risk of having children with a recessive genetic disorder.
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 and secreting apoB-containing lipoproteins. This, in turn, results in the inability to properly absorb and transport fats and fat soluble vitamins throughout the body. Therefore, a deficiency in MTP results in the absence of lipoproteins such as very low density lipoproteins (VLDLs), low density lipoproteins (LDLs), and chylomicrons in the blood. Lipoproteins are macromolecular complexes consisting of lipids and proteins. These lipid and protein complexes act as transporters that carry fats and fat soluble vitamins (e.g. vitamin E) throughout the body. The symptoms of abetalipoproteinemia are caused by the lack of these apoB-containing lipoproteins in the plasma.
Recent research has 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 MTP protein and the exact underlying mechanisms that cause disease in abetalipoproteinemia.
Additionally, several studies have shown that MTP is expressed in the heart and is involved in exporting lipids out of the heart. Low levels of MTP may lead to fat accumulation in the heart and affect heart function.
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. Abetalipoproteinemia affects both males and females. There are no known racial or ethnic preferences for the disorder. Abetalipoproteinemia is more prevalent in populations with a high incidence of consanguineous marriages. 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.
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 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 in the APOB, PCSK9, or ANGPTL3 genes and is inherited as an autosomal dominant trait. Contrary to abetalipoproteinemia, the presence of only one altered allele is sufficient to display symptoms of the disease.
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 indications. 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 (FRDA) is a genetic, progressive, neurodegerative movement disorder, with a mean age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling, and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop slurred speech (dysarthria), characteristic foot deformities; and irregular lateral or sideways curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure, which could present as shortness of breath upon exertion and chest pain. Some individuals may also experience irregularities in heart rhythm (cardiac arrhythmias). Some individuals may develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result primarily from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This results in secondary degeneration of nerve fibers in the spinal cord which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. FRDA is caused by abnormalities (mutations) in the FXN gene and people with FRDA inherit a mutation from each parent, so they have mutations in both copies of their FXN gene. This pattern, wherein parents who are clinically unaffected because they only carry a single mutant FXN gene but can have a child who is affected because he / she inherits a mutation from two carrier parents, is called autosomal recessive inheritance. (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.
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.
A complete neurological assessment, an eye examination, an endoscopy, and a liver (hepatic) ultrasound may be performed to evaluate the presence of potentially associated symptoms.
Molecular genetic testing to detect mutations in the MTTP gene is available to confirm the diagnosis.