Abetalipoproteinemia

National Organization for Rare Disorders, Inc.

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Important

It is possible that the main title of the report Abetalipoproteinemia is not the name you expected.

Disorder Subdivisions

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General Discussion

Summary

Abetalipoproteinemia is a rare inherited disorder 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.



Introduction

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.

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 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.



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. Thus, lipids and fat soluble vitamins are inadequately transported throughout the blood stream. In some cases, 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, 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 disabilities have been reported.



In some cases, the damage or malfunction of the peripheral nervous system (peripheral neuropathy) may occur. The peripheral nervous system contains all the nerves outside of the central nervous system. The associated symptoms can vary greatly from one person to another, but can include loss of proprioception (balance), 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, 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 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.



Patients may have fatty liver, which can cause liver damage. In rare cases, fibrosis or scarring of the liver (cirrhosis) has also been reported.

Causes

Abetalipoproteinemia is caused by mutations in the MTTP gene. These mutations are inherited as autosomal recessive traits. 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%.



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. Some individuals with abetalipoproteinemia have had parents who were blood relatives (consanguineous). This increases the risk of having children with a recessive genetic disorder.



Investigators have determined that the MTTP gene is located on the long arm (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 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 substances that consist of lipid and protein molecules. These lipid and protein complexes act as transporters that carry fats and fat soluble vitamins (i.e. 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.

Affected Populations

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.

Diagnosis

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 MTTP gene, but the test is only available on a clinical basis.



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.

Standard Therapies

Treatment



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, comprehensively, and collaboratively plan an affected child's treatment. Patients should be closely monitored every 6-12 months. Neurological and eye exams should be performed routinely to measure any ophthalmological or neurological deteriorations. Further, amino transaminases and albumin in the blood should be measured every year to determine if there is liver damage. Hepatic ultrasound can be performed to detect the presence of fatty liver. Echocardiography should be performed every three years to ensure the heart is working properly.



Most affected individuals respond to dietary therapy consisting of a diet low in fat especially long-chain saturated fatty acids. The reduction of the intake of dietary fats generally relieves gastrointestinal symptoms. Patients should receive frequent dietary counseling. Diets in infants may be supplemented with medium chain fatty acids, which can be transported in the blood without apoB-containing lipoproteins, in order to promote normal growth and development.



The oral 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 (i.e. tocopherol therapy) and vitamin A supplementation may prevent the neurological and retinal complications associated with abetalipoproteinemia. Vitamin D supplementation may help alleviate some of the symptoms associated with bone growth. Blood levels of fat soluble vitamins should be measured at each follow up because the blood levels do not always correlate with the amount of vitamins ingested. Doses should be adjusted based on the results of blood panels, neurological exams, and ophthalmological exams.



The prognosis of patients is highly variable. Early detection, treatment, and fat soluble vitamin supplementation can help curtail some of the neurological and ophthalmological deficiencies due to vitamin deficiency. Patients should be carefully monitored if receiving fat soluble drug treatments (i.e. for diseases unrelated to Abetalipoproteinemia) as their pharmacokinetics, absorption, and transport may also be affected. Additional treatment is symptomatic and supportive. Genetic counseling is recommended for families of children with abetalipoproteinemia.

Investigational Therapies

Gene therapy has 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 <a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>. 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

Email: <a href="mailto:prpl@cc.nih.gov" target="_blank">prpl@cc.nih.gov</a>



For information about clinical trials sponsored by private sources, in the main, contact:



<a href="http://www.centerwatch.com">www.centerwatch.com</a>



For information about clinical trials conducted in Europe, contact:



<a href="https://www.clinicaltrialsregister.eu/" target="_blank">https://www.clinicaltrialsregister.eu/</a>



Contact for additional information about abetalipoproteinemia:



Mahmood Hussain, Ph.D.

Department of Cell Biology and Pediatrics

SUNY Downstate Medical Center

Brooklyn, NY 11203

Email: <a href="mailto:mhussain@downstate.edu" target="_blank">mhussain@downstate.edu</a>

References

TEXTBOOKS



Min KHC, Pedley TA, Rowland LP. Neurologic Syndromes with Acanthocytes. In: Merritt's Neurology, 12th ed. Rowland LP, Pedley TA, editors. 2010 Lippincott Williams & Wilkins, Philadelphia, PA. pp. 665-668.



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



Di Filippo M, Moulin P, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61:891-902. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24842304">//www.ncbi.nlm.nih.gov/pubmed/24842304</a>



Lee, J. & Hegele, R. A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J. Inherit. Metab. Dis. 2014 May;37(3):333-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24288038">//www.ncbi.nlm.nih.gov/pubmed/24288038</a>



Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr Met. 2012; 9:14. <a href="http://www.ncbi.nlm.nih.gov/pubmed/22353470">//www.ncbi.nlm.nih.gov/pubmed/22353470</a>



Pons V, Rolland C, Nauze M, et al. A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein (MTTP). Hum Mutat. 2011;32:751-759. <a href="http://www.ncbi.nlm.nih.gov/pubmed/21394827">//www.ncbi.nlm.nih.gov/pubmed/21394827</a>



Sami MN, Sabbaghiam M, Mahjoob F, et al. Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia. Ann Hepatol. 2011;10:221-226. <a href="http://www.ncbi.nlm.nih.gov/pubmed/21502686">//www.ncbi.nlm.nih.gov/pubmed/21502686</a>



Zeissig S, Dougan SK, Barral DC, et al. Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. J Clin Invest. 2010;120:2889-2899. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912200/">//www.ncbi.nlm.nih.gov/pmc/articles/PMC2912200/</a>



Kassim SH, Wilson JM, Rader DJ. Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies. Clin Lipidol. 2010;5:793-809. <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324780/">//www.ncbi.nlm.nih.gov/pmc/articles/PMC3324780/</a>



Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;8:19. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18611256">//www.ncbi.nlm.nih.gov/pubmed/18611256</a>



Stevenson VL, Hardie RJ. Acanthocytosis and neurological disorders. J Neurol. 2001;248:87-94. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11284140">//www.ncbi.nlm.nih.gov/pubmed/11284140</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10940349">//www.ncbi.nlm.nih.gov/pubmed/10940349</a>



Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M. Microsomal triglyceride transfer protein and abetalipoproteinemia. Ann Endocrinol (Paris). 2000;61:125-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10940349">//www.ncbi.nlm.nih.gov/pubmed/10940349</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8533758">//www.ncbi.nlm.nih.gov/pubmed/8533758</a>



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. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8340987">//www.ncbi.nlm.nih.gov/pubmed/8340987</a>



INTERNET



Singh VN, Citkowitz E. Low LDL Cholesterol (Hypobetalipoproteinemia).Medscape. Updated: Dec 16, 2014. Available at: <a href="http://emedicine.medscape.com/article/121975-overview">//emedicine.medscape.com/article/121975-overview</a> Accessed July 20, 2015.



Benlian P. Abetalipoproteinemia. Orphanet Encyclopedia, May 2009. Available at: <a href="http://www.orpha.net/">//www.orpha.net/</a> Accessed July 20, 2015.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 200100; Last Update: 08/12/2014. Available at: <a href="http://omim.org/entry/200100">//omim.org/entry/200100</a> Accessed July 20, 2015.

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