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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S
Synonyms and keywords: Acanthocytosis, Bassen-Kornzweig syndrome, apolipoprotein B deficiency, microsomal triglyceride transfer protein deficiency, MTP deficiency
Abetalipoproteinemia is a very rare autosomal recessive disease due to mutation in MTP gene on chromosome 4q23. MTP encodes for microsomal triglyceride transport protein, which catalyses the intracellular transport of triglyceride, cholesterol esters and phospholipids from the cytosol onto the apolipoprotein B present in the endoplasmic reticulum. Mutation in MTP gene results in the failure of formation and secretion of chylomicrons, LDL and VLDL which accumulate in the intestine and liver. Characteristic features of abetalipoproteinemia include steatorrhea, retinitis pigmentosa, ataxia, acanthocytosis, low or undetectable LDL and apolipoprotein B. Patients present in infancy with steatorrhea and failure to thrive. Asymptomatic patients in infancy are usually diagnosed in adulthood with symptoms of neuropathy. Fat malabsorption results in the deficiency of fat soluble vitamins and essential fatty acids, features of vitamin E deficiency are seen early in the disease, as the vitamin E levels are dependent on the total lipid levels in the body. Early diagnosis and initiation of vitamin E supplementation is helpful to stop the progression of disease and in reversal of neurological damage.
- The first clinical association of peripheral blood acanthocytosis, atypical retinitis pigmentosa and ataxia was reported by Bassen and Kornzweig in 1950.
- In 1958, Jampel and Falls observed low serum cholesterol values in affected individuals.
- In 1960, Salt noticed the absence of serum beta-lipoprotein in the patient on electrophoresis.
- The biochemical defect was determined to be a complete absence of apolipoprotein B-containing lipoproteins: chylomicrons, very-low density lipoprotein (VLDL), and low-density lipoprotein (LDL).
- In 1986, apolipoprotein B content of the hepatocytes, APOB gene and mRNA were found to be normal in patients with abetalipoproteinemia, suggesting a defective post-translational processing and secretion of apolipoprotein B as the cause of abetalipoproteinemia.
- In 1992, microsomal triglyceride transfer protein (MTP) a deficiency due to the mutation reported as the primary cause of abetalipoproteinemia.
- In 1993, the region on chromosome 4q 22-24 that encodes the large sub-unit of MTP was cloned and sequenced, and various human MTP mutations in abetalipoproteinemia patients were reported.
- MTTP catalyzes the transfer of triglycerides from the cytosol to apolipoprotein B in the endoplasmic reticulum, essential step for the formation and secretion of LDL, VLDL, and chylomicrons.
- Abetalipoproteinemia is a defect in the MTP, the mutation causes defective intracellular lipid transport resulting in the accumulation of lipids in the intestine, leading to steatorrhea, malabsorption of fat soluble vitamins and accumulation of lipids in the liver causing hepatic steatosis.
- Excessive accumulation of lipid in the liver and intestine results in very low LDL and VLDL.
- Vitamin E deficiency features are more prominent because the absorption and transport of vitamin E are parallel to the total body lipid levels, due to its hydrophobic nature. Spinocerebellar and posterior columns of the spinal cord are affected as only minimal amount of vitamin E is transported in HDL causing demyelination.
- Abetalipoproteinemia is transmitted in an autosomal recessive inheritance pattern.
- Abetalipoproteinemia is caused by a mutation in MTP (aka MTTP) gene which codes for the microsomal trigyceride transfer protein on chromosome 4q 22-24. 
- MTTP gene mutation results in defective intracellular transport leading to the failure of formation and secretion of apolipoprotein B containing lipoproteins which include chylomicrons, LDL and VLDL from the intestine and liver.
- Patients with heterozygous expression have normal lipoprotein levels indicating that both the alleles of the gene must be defective to cause the disease.
On microscopic examination:
- Intestinal biopsy demonstrates distended enterocytes strongly positive to oil red O indicating the presence of intracellular lipid.
- Liver biopsy demonstrates hepatic steatosis.
- Screening for the disease is advised for prenatal diagnosis who are known heterozygous carriers for the disease.
Epidemiology and Demographics
- Worldwide, the prevalence of abetalipoproteinemia is reported to be less than 1 in 1,000,000.
- Males and females are affected equally.
Natural History, Complications, and Prognosis
- If left untreated, patients can develop atypical retinitis pigmentosa, severe ataxia, dysarthria, and absent reflexes, leading to significant neurological functional impairment and reduced lifespan.
- Early identification and treatment with vitamin E can delay and prevent progression of the disease. 
- The prognosis is poor with a significantly reduced life expectancy.
Clinical diagnosis is made based on the symptoms, lipid profile and peripheral blood smear findings.
History and Symptoms
- Patients present in infancy with symptoms of chronic diarrhea, steatorrhea, failure to thrive.
- The neurological symptoms due to demyelination, which begins in the first or second decade of life and include:
- Progressive truncal ataxia : Presents as instability
- Peripheral neuropathy causing numbness, tingling, weakness and parasthesias.
- Less common symptoms in abetalipoproteinemia due to long term fat soluble vitamin deficiency include:
- Easy bruising
- Loss of night vision is the first symptom of retinal degeneration which progresses to blindness.
Physical examination of patients with abetalipoproteinemia is remarkable for:
- Ophthalmologic findings, include reduced visual acuity and degenerative changes in the retina.
- Neurological findings include:
- Truncal ataxia due to the effect on spinocerebellar tracts.
- Muscle atrophy and weakness due to motor neuropathy.
- Loss of proprioception, vibration and temperature when the disease affects the posterior column.
- Deep tendon reflexes are diminished.
Laboratory findings consistent with the diagnosis of abetalipoproteinemia include :
- Lipid profile after a 12 hour fast will demonstrate a low LDLC less than 0.1 mmol/L and triglyceride level of <0.2 mmol/L.
- Very low or undetectable vitamin E levels.
- Elevated liver function tests due to hepatic steatosis.
- Hepatomegaly can be demonstrated on abdominal ultrasound.
- Peripheral blood smear demonstrates 50 to 90% of acanthocytes, with increased erythrocyte fragility.
- Absent beta-lipoprotein is demonstrated on 2D electrophoresis.(apo B (<0.1 g/L)
- Gold standard test for diagnosing abetalipoproteinemia is molecular gene sequencing for MTTP gene.
Approach to Low LDL C Algorithm
The following algorithm helps to diagnose patients with low LDL C:
|Low LDL C <5th percentile|
|Rule out secondary causes of low LDL |
Chronic liver disease
|Consider primary monogenic causes based on lipid profile|
|Normal Triglycerides||Low Triglycerides|
|Chlyomicron retention disease |
(Confirm with gene sequencing)
|Screen the lipid profile of the patient's parents|
|Normal Parental Lipid Profile||If Parental Lipid profile <50% of Normal on:|
(Confirm with gene sequencing)
|Familial homozygous hypobetalipoproteinemia|
(Confirm with gene sequencing)
Initial approach to a patient with steatorrhea requires a general approach to rule out the congenital causes of diarrhea and then consider the rarer causes like abetalipoproteinemia. 
The table below summarizes the diseases that have similar presentation as abetalipoproteinemia:
|Vitamin E deficiency
secondary to fat malabsorption
The main stay of medical therapy for abetalipoproteinemia is fat soluble vitamin supplementation, monitoring the progression of growth, and early identification and treatment of complications.
- High dose oral vitamin E supplementation therapy, 150-300mg/kg/day helps in preventing and reversal of neurological symptoms.
- Dosing and efficacy can be assessed by checking the Vitamin E levels in the adipose tissue needle aspiration biopsy. 
- Oral supplementation of Vitamin A 100–400 IU/kg/day; Vitamin D 800–1200 IU/day; Vitamin K 5–35 mg/week.
- Parental supplementation of fat soluble vitamins is not preferred due to the risk of hepatic steatosis.
- Diet modification is advised for control gastrointestinal symptoms, low fat diet consisting of less than 30 % of daily requirement with reduced long-chain fatty acids and oral essential fatty acids is recommended.
Surgical intervention is not recommended for the management of abetalipoproteinemia.
There are no primary preventive measures available for abetalipoproteinemia.
Secondary prevention strategies following abetalipoproteinemia include:
- Monitoring growth in children and to delay neurological complications.
- Assessment for ataxia, dysarthria, visual changes every 6 to 12 months.
- As vitamin levels do not return to normal even after years of treatment, it's recommended to assess for features of deficiency regularly.
- ↑ BASSEN FA, KORNZWEIG AL (1950). "Malformation of the erythrocytes in a case of atypical retinitis pigmentosa". Blood. 5 (4): 381–87. PMID 15411425.
- ↑ JAMPEL RS, FALLS HF (1958). "Atypical retinitis pigmentosa, acanthrocytosis, and heredodegenerative neuromuscular disease". AMA Arch Ophthalmol. 59 (6): 818–20. PMID 13532088.
- ↑ SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV (1960). "On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea". Lancet. 2 (7146): 325–9. PMID 13745738.
- ↑ 4.0 4.1 Sturman RM (1968). "The Bassen-Kornzweig syndrome: 18 years in evolution". J Mt Sinai Hosp N Y. 35 (5): 489–517. PMID 5245476.
- ↑ 5.0 5.1 Lackner KJ, Monge JC, Gregg RE, Hoeg JM, Triche TJ, Law SW; et al. (1986). "Analysis of the apolipoprotein B gene and messenger ribonucleic acid in abetalipoproteinemia". J Clin Invest. 78 (6): 1707–12. doi:10.1172/JCI112766. PMC 423946. PMID 3782476.
- ↑ 6.0 6.1 Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M; et al. (1992). "Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia". Science. 258 (5084): 999–1001. PMID 1439810.
- ↑ 7.0 7.1 Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT; et al. (1993). "Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein". Hum Mol Genet. 2 (12): 2109–16. PMID 8111381.
- ↑ 8.0 8.1 Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR (2000). "The role of the microsomal triglygeride transfer protein in abetalipoproteinemia". Annu Rev Nutr. 20: 663–97. doi:10.1146/annurev.nutr.20.1.663. PMID 10940349.
- ↑ Bjornson LK, Kayden HJ, Miller E, Moshell AN (1976). "The transport of alpha-tocopherol and beta-carotene in human blood". J Lipid Res. 17 (4): 343–52. PMID 181502.
- ↑ Lee J, Hegele RA (2014). "Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management". J Inherit Metab Dis. 37 (3): 333–9. doi:10.1007/s10545-013-9665-4. PMID 24288038.
- ↑ Burnett JR, Bell DA, Hooper AJ, Hegele RA (2015). "Clinical utility gene card for: Abetalipoproteinaemia--Update 2014". Eur J Hum Genet. 23 (6). doi:10.1038/ejhg.2014.224. PMC 4795071. PMID 25335492.
- ↑ Walsh MT, Iqbal J, Josekutty J, Soh J, Di Leo E, Özaydin E; et al. (2015). "Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function". Circ Cardiovasc Genet. 8 (5): 677–87. doi:10.1161/CIRCGENETICS.115.001106. PMC 4618089. PMID 26224785.
- ↑ Hussain MM, Rava P, Walsh M, Rana M, Iqbal J (2012). "Multiple functions of microsomal triglyceride transfer protein". Nutr Metab (Lond). 9: 14. doi:10.1186/1743-7075-9-14. PMC 3337244. PMID 22353470.
- ↑ 14.0 14.1 "Orphanet: Abetalipoproteinemia".
- ↑ Burnett JR, Bell DA, Hooper AJ, Hegele RA (2012). "Clinical utility gene card for: Abetalipoproteinaemia". Eur J Hum Genet. 20 (8). doi:10.1038/ejhg.2012.30. PMC 3400737. PMID 22378282.
- ↑ Chowers I, Banin E, Merin S, Cooper M, Granot E (2001). "Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients". Eye (Lond). 15 (Pt 4): 525–30. doi:10.1038/eye.2001.167. PMID 11767031.
- ↑ Hegele RA, Angel A (1985). "Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy". Can Med Assoc J. 132 (1): 41–4. PMC 1346503. PMID 2981135.
- ↑ "Orphanet: Abetalipoproteinemia".
- ↑ SOBREVILLA LA, GOODMAN ML, KANE CA (1964). "DEMYELINATING CENTRAL NERVOUS SYSTEM DISEASE, MACULAR ATROPHY AND ACANTHOCYTOSIS (BASSEN-KORNZWEIG SYNDROME)". Am J Med. 37: 821–8. PMID 14237436.
- ↑ Runge P, Muller DP, McAllister J, Calver D, Lloyd JK, Taylor D (1986). "Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia". Br J Ophthalmol. 70 (3): 166–73. PMC 1040960. PMID 3954973.
- ↑ Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S; et al. (2014). "Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia". J Hepatol. 61 (4): 891–902. doi:10.1016/j.jhep.2014.05.023. PMID 24842304.
- ↑ Terrin G, Tomaiuolo R, Passariello A, Elce A, Amato F, Di Costanzo M; et al. (2012). "Congenital diarrheal disorders: an updated diagnostic approach". Int J Mol Sci. 13 (4): 4168–85. doi:10.3390/ijms13044168. PMC 3344208. PMID 22605972.
- ↑ Overeem AW, Posovszky C, Rings EH, Giepmans BN, van IJzendoorn SC (2016). "The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders". Dis Model Mech. 9 (1): 1–12. doi:10.1242/dmm.022269. PMC 4728335. PMID 26747865.
- ↑ 24.0 24.1 Jung HH, Danek A, Walker RH (2011). "Neuroacanthocytosis syndromes". Orphanet J Rare Dis. 6: 68. doi:10.1186/1750-1172-6-68. PMC 3212896. PMID 22027213.
- ↑ Rezende TJ, Silva CB, Yassuda CL, Campos BM, D'Abreu A, Cendes F; et al. (2016). "Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia". Mov Disord. 31 (1): 70–8. doi:10.1002/mds.26436. PMID 26688047.
- ↑ Ching KH, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ (2002). "HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration". Neurology. 58 (11): 1673–4. PMID 12058097.
- ↑ Muller DP, Lloyd JK (1982). "Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia". Ann N Y Acad Sci. 393: 133–44. PMID 6959555.
- ↑ Iqbal J, Hussain MM (2009). "Intestinal lipid absorption". Am J Physiol Endocrinol Metab. 296 (6): E1183–94. doi:10.1152/ajpendo.90899.2008. PMC 2692399. PMID 19158321.
- ↑ 29.0 29.1 Muller DP, Lloyd JK, Bird AC (1977). "Long-term management of abetalipoproteinaemia. Possible role for vitamin E." Arch Dis Child. 52 (3): 209–14. PMC 1546285. PMID 848999.
- ↑ Cavicchi M, Crenn P, Beau P, Degott C, Boutron MC, Messing B (1998). "Severe liver complications associated with long-term parenteral nutrition are dependent on lipid parenteral input". Transplant Proc. 30 (6): 2547. PMID 9745481.
- ↑ Zamel R, Khan R, Pollex RL, Hegele RA (2008). "Abetalipoproteinemia: two case reports and literature review". Orphanet J Rare Dis. 3: 19. doi:10.1186/1750-1172-3-19. PMC 2467409. PMID 18611256.