Abetalipoproteinemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and Keywords: Acanthocytosis, Bassen-Kornzweig syndrome, apolipoprotein B deficiency, microsomal triglyceride transfer protein deficiency, MTP deficiency

Overview

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.

Historical Perspective

Pathophysiology

Pathogenesis

Genetics

Microscopic Findings

On microscopic examination:

Screening

Epidemiology and Demographics

  • Worldwide, the prevalence of abetalipoproteinemia is reported to be less than 1 in 1,000,000.[15]
  • 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.[14]
  • Early identification and treatment with vitamin E can delay and prevent progression of the disease.[16] [17]
  • The prognosis is poor with a significantly reduced life expectancy.[18]

Diagnosis

Clinical diagnosis is made based on the symptoms, lipid profile and peripheral blood smear findings.

History and Symptoms

Physical Examination

Physical examination of patients with abetalipoproteinemia is remarkable for:

Laboratory Findings

Laboratory findings consistent with the diagnosis of abetalipoproteinemia include :

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
Anemia
Criticial illness
Chronic inflammation
Chronic liver disease
Hyperthyroidism
Infection
Malabsorption
Malignancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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:
*LDL
*Total Cholesterol
*Triglycerides
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abetalipoproteinemia
(Confirm with gene sequencing)
 
 
Familial homozygous hypobetalipoproteinemia
(Confirm with gene sequencing)

Differential Diagnosis

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.[22] [23]

The table below summarizes the diseases that have similar presentation as abetalipoproteinemia[24]:

Disease Findings
Abetalipoproteinemia
Autosomal recessive
Hypobetalipoproteinemia
Autosomal co-dominant
Fredrich Ataxia
Autosomal recessive
Vitamin E deficiency
secondary to fat malabsorption
McLeod Syndrome
X-linked recessive
HARP syndrome
Autosomal recessive

Treatment

Medical Therapy

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.

Surgery

Surgical intervention is not recommended for the management of abetalipoproteinemia.

Primary Prevention

There are no primary preventive measures available for abetalipoproteinemia.

Secondary Prevention

Secondary prevention strategies following abetalipoproteinemia include:

  • Monitoring growth in children and to delay neurological complications.[29]
  • 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.[31]

References

  1. BASSEN FA, KORNZWEIG AL (1950). "Malformation of the erythrocytes in a case of atypical retinitis pigmentosa.". Blood. 5 (4): 381–87. PMID 15411425. 
  2. JAMPEL RS, FALLS HF (1958). "Atypical retinitis pigmentosa, acanthrocytosis, and heredodegenerative neuromuscular disease.". AMA Arch Ophthalmol. 59 (6): 818–20. PMID 13532088. 
  3. 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. 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. 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. PMC 423946Freely accessible. PMID 3782476. doi:10.1172/JCI112766. 
  6. 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. 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. 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. PMID 10940349. doi:10.1146/annurev.nutr.20.1.663. 
  9. 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. 
  10. Lee J, Hegele RA (2014). "Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.". J Inherit Metab Dis. 37 (3): 333–9. PMID 24288038. doi:10.1007/s10545-013-9665-4. 
  11. Burnett JR, Bell DA, Hooper AJ, Hegele RA (2015). "Clinical utility gene card for: Abetalipoproteinaemia--Update 2014.". Eur J Hum Genet. 23 (6). PMC 4795071Freely accessible. PMID 25335492. doi:10.1038/ejhg.2014.224. 
  12. 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. PMC 4618089Freely accessible. PMID 26224785. doi:10.1161/CIRCGENETICS.115.001106. 
  13. Hussain MM, Rava P, Walsh M, Rana M, Iqbal J (2012). "Multiple functions of microsomal triglyceride transfer protein.". Nutr Metab (Lond). 9: 14. PMC 3337244Freely accessible. PMID 22353470. doi:10.1186/1743-7075-9-14. 
  14. 14.0 14.1 "Orphanet: Abetalipoproteinemia". 
  15. Burnett JR, Bell DA, Hooper AJ, Hegele RA (2012). "Clinical utility gene card for: Abetalipoproteinaemia.". Eur J Hum Genet. 20 (8). PMC 3400737Freely accessible. PMID 22378282. doi:10.1038/ejhg.2012.30. 
  16. 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. PMID 11767031. doi:10.1038/eye.2001.167. 
  17. 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 1346503Freely accessible. PMID 2981135. 
  18. "Orphanet: Abetalipoproteinemia". 
  19. 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. 
  20. 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 1040960Freely accessible. PMID 3954973. 
  21. 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. PMID 24842304. doi:10.1016/j.jhep.2014.05.023. 
  22. 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. PMC 3344208Freely accessible. PMID 22605972. doi:10.3390/ijms13044168. 
  23. 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. PMC 4728335Freely accessible. PMID 26747865. doi:10.1242/dmm.022269. 
  24. 24.0 24.1 Jung HH, Danek A, Walker RH (2011). "Neuroacanthocytosis syndromes.". Orphanet J Rare Dis. 6: 68. PMC 3212896Freely accessible. PMID 22027213. doi:10.1186/1750-1172-6-68. 
  25. 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. PMID 26688047. doi:10.1002/mds.26436. 
  26. 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. 
  27. 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. 
  28. Iqbal J, Hussain MM (2009). "Intestinal lipid absorption.". Am J Physiol Endocrinol Metab. 296 (6): E1183–94. PMC 2692399Freely accessible. PMID 19158321. doi:10.1152/ajpendo.90899.2008. 
  29. 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 1546285Freely accessible. PMID 848999. 
  30. 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. 
  31. Zamel R, Khan R, Pollex RL, Hegele RA (2008). "Abetalipoproteinemia: two case reports and literature review.". Orphanet J Rare Dis. 3: 19. PMC 2467409Freely accessible. PMID 18611256. doi:10.1186/1750-1172-3-19. 

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