Abetalipoproteinemia: Difference between revisions

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{{SI}}
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{{CMG}} {{AE}} {{AKI}}
'''To view Lipoprotein Disorders Main Page [[ Lipoprotein disorders| Click here]]'''<br>
'''To view Hypolipoproteinemia Main Page [[ Hypolipoproteinemia | Click here]]''' <br>
{{CMG}}; {{AE}} {{AKI}}


{{SK}} Acanthocytosis, Bassen-Kornzweig syndrome, apolipoprotein B deficiency, microsomal triglyceride transfer protein deficiency, MTP deficiency
{{SK}} Acanthocytosis, Bassen-Kornzweig syndrome, apolipoprotein B deficiency, microsomal triglyceride transfer protein deficiency, MTP deficiency
==History Perspective==


==Overview==
==Overview==
Abetalipoproteinemia is a very rare [[autosomal recessive]] disease due to mutation in [[MTPN|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 [[Very low density lipoprotein|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.


It is a disease with autosomal recessive inheritance, affecting the etc.
==Historical Perspective==
Abetalipoproteinemia and hypobetalipoproteinemia together are reffered to as familial hypolipoproteinemia. These are a set of diseases which specifically have low LDL C levels.
*The first clinical association of peripheral [[blood]] [[acanthocytosis]], atypical [[retinitis pigmentosa]] and [[ataxia]] was reported by Bassen and Kornzweig in 1950.<ref name="pmid15411425">{{cite journal| author=BASSEN FA, KORNZWEIG AL| title=Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. | journal=Blood | year= 1950 | volume= 5 | issue= 4 | pages= 381-87 | pmid=15411425 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15411425  }} </ref>
*In 1958, Jampel and Falls observed low [[serum]] [[cholesterol]] values in affected individuals.<ref name="pmid13532088">{{cite journal| author=JAMPEL RS, FALLS HF| title=Atypical retinitis pigmentosa, acanthrocytosis, and heredodegenerative neuromuscular disease. | journal=AMA Arch Ophthalmol | year= 1958 | volume= 59 | issue= 6 | pages= 818-20 | pmid=13532088 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13532088  }} </ref>
*In 1960, Salt noticed the absence of [[serum]] beta-[[lipoprotein]] in the patient on [[electrophoresis]].<ref name="pmid13745738">{{cite journal| author=SALT HB, WOLFF OH, LLOYD JK, FOSBROOKE AS, CAMERON AH, HUBBLE DV| title=On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea. | journal=Lancet | year= 1960 | volume= 2 | issue= 7146 | pages= 325-9 | pmid=13745738 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13745738  }} </ref>
*The biochemical defect was determined to be a complete absence of [[apolipoprotein B]]-containing [[lipoproteins]]: [[Chylomicron|chylomicrons]], very-low density lipoprotein ([[VLDL]]), and low-density lipoprotein ([[LDL]]).<ref name="pmid5245476">{{cite journal| author=Sturman RM| title=The Bassen-Kornzweig syndrome: 18 years in evolution. | journal=J Mt Sinai Hosp N Y | year= 1968 | volume= 35 | issue= 5 | pages= 489-517 | pmid=5245476 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5245476  }} </ref>
* 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.<ref name="pmid3782476">{{cite journal| author=Lackner KJ, Monge JC, Gregg RE, Hoeg JM, Triche TJ, Law SW et al.| title=Analysis of the apolipoprotein B gene and messenger ribonucleic acid in abetalipoproteinemia. | journal=J Clin Invest | year= 1986 | volume= 78 | issue= 6 | pages= 1707-12 | pmid=3782476 | doi=10.1172/JCI112766 | pmc=423946 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3782476  }} </ref>
*In 1992, [[Microsomal triglyceride transfer protein deficiency|microsomal triglyceride transfer protein]] (MTP) a deficiency due to the mutation reported as the primary cause of abetalipoproteinemia.<ref name="pmid1439810">{{cite journal| author=Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M et al.| title=Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. | journal=Science | year= 1992 | volume= 258 | issue= 5084 | pages= 999-1001 | pmid=1439810 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1439810  }} </ref>
*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.<ref name="pmid8111381">{{cite journal| author=Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT et al.| title=Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. | journal=Hum Mol Genet | year= 1993 | volume= 2 | issue= 12 | pages= 2109-16 | pmid=8111381 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8111381  }} </ref>


==Pathophysiology==
==Pathophysiology==
=== Pathogenesis ===
*MTTP catalyzes the transfer of [[triglycerides]] from the [[cytosol]] to [[ApoB|apolipoprotein B]] in the [[endoplasmic reticulum]], essential step for the formation and secretion of [[LDL]], [[VLDL]], and [[chylomicrons]].<ref name="pmid10940349">{{cite journal| author=Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR| title=The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. | journal=Annu Rev Nutr | year= 2000 | volume= 20 | issue=  | pages= 663-97 | pmid=10940349 | doi=10.1146/annurev.nutr.20.1.663 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10940349  }} </ref>
*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 tract|Spinocerebellar]] and [[posterior columns]] of the [[spinal cord]] are affected as only minimal amount of [[vitamin E]] is transported in [[HDL]] causing [[demyelination]].<ref name="pmid181502">{{cite journal| author=Bjornson LK, Kayden HJ, Miller E, Moshell AN| title=The transport of alpha-tocopherol and beta-carotene in human blood. | journal=J Lipid Res | year= 1976 | volume= 17 | issue= 4 | pages= 343-52 | pmid=181502 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=181502  }} </ref>


*Autosomal Recessive Inheritance.
===Genetics===
*Deletion of gene which codes for the Microsomal Trigyceride transfer Protien, MTP.
*Abetalipoproteinemia is transmitted in an [[autosomal recessive]] inheritance pattern.<ref name="pmid24288038">{{cite journal| author=Lee J, Hegele RA| title=Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. | journal=J Inherit Metab Dis | year= 2014 | volume= 37 | issue= 3 | pages= 333-9 | pmid=24288038 | doi=10.1007/s10545-013-9665-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24288038  }} </ref><ref name="pmid25335492">{{cite journal| author=Burnett JR, Bell DA, Hooper AJ, Hegele RA| title=Clinical utility gene card for: Abetalipoproteinaemia--Update 2014. | journal=Eur J Hum Genet | year= 2015 | volume= 23 | issue= 6 | pages=  | pmid=25335492 | doi=10.1038/ejhg.2014.224 | pmc=4795071 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25335492  }} </ref>
*MTP mutation leads to the failure of formation and secretion of apolipoprotein B( Apo B)containing lipoproteins which include chylomicrons, LDL and VLDL from the intestine and liver.
*Abetalipoproteinemia is caused by a [[mutation]] in MTP (aka MTTP) gene which codes for the [[microsomal trigyceride transfer protein]] on [[chromosome]] 4q 22-24.<ref name="pmid8111381" /> <ref name="pmid1439810">{{cite journal| author=Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M et al.| title=Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. | journal=Science | year= 1992 | volume= 258 | issue= 5084 | pages= 999-1001 | pmid=1439810 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1439810  }} </ref><ref name="pmid26224785">{{cite journal| author=Walsh MT, Iqbal J, Josekutty J, Soh J, Di Leo E, Özaydin E et al.| title=Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function. | journal=Circ Cardiovasc Genet | year= 2015 | volume= 8 | issue= 5 | pages= 677-87 | pmid=26224785 | doi=10.1161/CIRCGENETICS.115.001106 | pmc=4618089 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26224785  }} </ref>
*Chylomicron formation failure causes Steatorrhea and malabsorption of fat soluble vitamins.  
*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]].<ref name="pmid22353470">{{cite journal| author=Hussain MM, Rava P, Walsh M, Rana M, Iqbal J| title=Multiple functions of microsomal triglyceride transfer protein. | journal=Nutr Metab (Lond) | year= 2012 | volume= 9 | issue=  | pages= 14 | pmid=22353470 | doi=10.1186/1743-7075-9-14 | pmc=3337244 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22353470  }} </ref>
*Vitamin E deficiency is more prominent because the absorption and transport of vitamin E is parallel to the total body lipid levels due to its hydrophobic
*Patients with [[heterozygous]] expression have normal [[lipoprotein]] levels indicating that both the [[Allele|alleles]] of the gene must be defective to cause the disease.
nature.
*Spinocerebellar and posterior columns are affected as only minimal amount of vitamin E was transported in HDL C resulting in neurological symptoms.


==Clinical Features==
===Microscopic Findings===
*Patients present in the early childhood with chronic diaarhea, steatorrhea and failure to thrive.
On microscopic examination:
*Symptoms progress with age and neurological symptoms appear in early adolescence include progressive ataxia, visual defects and peripheral neuropathy.
*Intestinal biopsy demonstrates distended [[enterocytes]] strongly positive to [[Oil Red O|oil red O]] indicating the presence of intracellular [[lipid]].<ref name="pmid10940349">{{cite journal| author=Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR| title=The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. | journal=Annu Rev Nutr | year= 2000 | volume= 20 | issue=  | pages= 663-97 | pmid=10940349 | doi=10.1146/annurev.nutr.20.1.663 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10940349  }} </ref>
*[[Liver]] [[biopsy]] demonstrates [[hepatic steatosis]].


==Physical Examination==
== Screening==
Specific physical exam findings include as follows:
*Screening for the disease is advised for [[prenatal diagnosis]] who are known [[heterozygous]] carriers for the disease.<ref name="urlOrphanet: Abetalipoproteinemia">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=252&Disease_Disease_Search_diseaseGroup=Abetalipoproteinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Abetalipoproteinemia&title=Abetalipoproteinemia&search=Disease_Search_Simple |title=Orphanet: Abetalipoproteinemia |format= |work= |accessdate=}}</ref>


*EYE: Reduced Visual Acuity and degenerative changes in the retina secondary to Vitamin A deficiency.
== Epidemiology and Demographics ==
*Neurological:  
*Worldwide, the [[prevalence]] of abetalipoproteinemia is reported to be less than 1 in 1,000,000.<ref name="pmid22378282">{{cite journal| author=Burnett JR, Bell DA, Hooper AJ, Hegele RA| title=Clinical utility gene card for: Abetalipoproteinaemia. | journal=Eur J Hum Genet | year= 2012 | volume= 20 | issue= 8 | pages=  | pmid=22378282 | doi=10.1038/ejhg.2012.30 | pmc=3400737 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22378282  }} </ref>
**Truncal Ataxia due to the effect on spinocerebellar tracts.
*Males and females are affected equally.
**Sensory Motor neuropathy presenting with weakness and muscular atrophy.
 
**Loss of proprioception, vibration and temperature can be affected when the disease affects the posterior column.
== Natural History, Complications, and Prognosis ==
**Reflexes can be present or reduced.
*If left untreated, patients can develop atypical [[retinitis pigmentosa]], severe [[ataxia]], [[dysarthria]], and absent reflexes, leading to significant neurological functional impairment and reduced lifespan.<ref name="urlOrphanet: Abetalipoproteinemia">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=252&Disease_Disease_Search_diseaseGroup=Abetalipoproteinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Abetalipoproteinemia&title=Abetalipoproteinemia&search=Disease_Search_Simple |title=Orphanet: Abetalipoproteinemia |format= |work= |accessdate=}}</ref>
*Early identification and treatment with [[vitamin E]] can delay and prevent progression of the disease.<ref name="pmid11767031">{{cite journal| author=Chowers I, Banin E, Merin S, Cooper M, Granot E| title=Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. | journal=Eye (Lond) | year= 2001 | volume= 15 | issue= Pt 4 | pages= 525-30 | pmid=11767031 | doi=10.1038/eye.2001.167 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11767031  }} </ref> <ref name="pmid2981135">{{cite journal| author=Hegele RA, Angel A| title=Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose vitamin E therapy. | journal=Can Med Assoc J | year= 1985 | volume= 132 | issue= 1 | pages= 41-4 | pmid=2981135 | doi= | pmc=1346503 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2981135  }} </ref>
*The [[prognosis]] is poor with a significantly reduced life expectancy.<ref name="urlOrphanet: Abetalipoproteinemia2">{{cite web |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=252&Disease_Disease_Search_diseaseGroup=Abetalipoproteinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Abetalipoproteinemia&title=Abetalipoproteinemia&search=Disease_Search_Simple |title=Orphanet: Abetalipoproteinemia |format= |work= |accessdate=}}</ref>


==Diagnosis==
==Diagnosis==
Characteristic labs include :
Clinical diagnosis is made based on the symptoms, [[lipid profile]] and [[ peripheral blood smear]] findings.


*Low Triglyceride and total cholesterol levels.
===History and Symptoms===
*Absent Beta-lipoprotien on electrophoresis is the diagnostic test, Genetic testing for MTP gene is not available.
*Patients present in [[infancy]] with symptoms of [[Chronic diarrhea resident survival guide|chronic diarrhea]], [[steatorrhea]], [[failure to thrive]].
*Peripheral Smear shows 50 to 90% of acanthocytes.
*The neurological symptoms due to [[demyelination]], which begins in the first or second decade of life and include:
*Nerve conduction studies show reduced or absent action potential.
**Progressive truncal [[ataxia]] : Presents as instability 
*Very low or Undetectable vitamin E levels.
**Peripheral [[neuropathy]] causing [[numbness]], [[tingling]], weakness and [[parasthesias]].<ref name="pmid14237436">{{cite journal| author=SOBREVILLA LA, GOODMAN ML, KANE CA| title=DEMYELINATING CENTRAL NERVOUS SYSTEM DISEASE, MACULAR ATROPHY AND ACANTHOCYTOSIS (BASSEN-KORNZWEIG SYNDROME). | journal=Am J Med | year= 1964 | volume= 37 | issue=  | pages= 821-8 | pmid=14237436 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14237436  }} </ref>
*Elevated LFT's due to hepatic steatosis.
*Less common symptoms  in abetalipoproteinemia due to long term [[fat soluble vitamin]] deficiency include:
*Impaired ACTH response to cortisol in homozygotes.
**Easy [[bruising]]
**Loss of night vision is the first symptom of [[retinal degeneration]] which progresses to [[blindness]].
**[[Osteomalacia]]


==Differential Diagnosis==
===Physical Examination===
*Hypobetalipoproteinemia: Clinical Features, peripheral smear and lipid analysis are similar.
Physical examination of patients with abetalipoproteinemia is remarkable for:  
*Severe Vitamin E deficiency: Neurological Symptoms improve significantly with supplementation of Vitamin E.
*Friedrich Ataxia.


==Treatment==
*Ophthalmologic findings, include reduced [[visual acuity]] and degenerative changes in the [[retina]].
*Vitamin E Supplementation, 150mg/kg/day helps in preventing or reversal of the neurological symptoms. Dosing and efficacy can be assessed by checking the Vitamin E levels in the adipose tissue needle aspiration biopsy.
**Fundoscopic examination reveal expanding [[Scotoma|scotomas]], which left untreated will result in [[blindness]]. <ref name="pmid3954973">{{cite journal| author=Runge P, Muller DP, McAllister J, Calver D, Lloyd JK, Taylor D| title=Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia. | journal=Br J Ophthalmol | year= 1986 | volume= 70 | issue= 3 | pages= 166-73 | pmid=3954973 | doi= | pmc=1040960 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3954973  }} </ref>
* Fat soluble vitamins( A, K and D) supplementation.
*[[Hepatomegaly]]
*Diet modification to control gastrointestinal symptoms.
*Neurological findings include:
**[[Truncal ataxia]] due to the effect on [[spinocerebellar tract]]s.
**[[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.


==Hypobetalipoproteinemia==
===Laboratory Findings===
It shares similar clinical and lab features with abetalipoproteinemia.
Laboratory findings consistent with the diagnosis of abetalipoproteinemia include :
===Pathophysiology and Lab Findings===
*Mutations in the gene coding for Apolipoprotein B resulting in malabsorption, hepatic steatosis and fat souble vitamin deficiency.
*Genetics:
**Based on a Study which involved genetic analysis in 2010, showed
***
***
***


*Patients commonly have low levels of plasma ApoB and LDL cholesterol.
*[[Lipid profile]] after a 12 hour fast will demonstrate a low [[LDL]]C less than 0.1 mmol/L and [[triglyceride]] level of <0.2 mmol/L.<ref name="pmid5245476">{{cite journal| author=Sturman RM| title=The Bassen-Kornzweig syndrome: 18 years in evolution. | journal=J Mt Sinai Hosp N Y | year= 1968 | volume= 35 | issue= 5 | pages= 489-517 | pmid=5245476 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5245476  }} </ref>
*Very low or undetectable [[vitamin E]] levels.
*Elevated [[liver function test]]s due to [[hepatic steatosis]].
**[[Hepatomegaly]] can be demonstrated on abdominal [[ultrasound]].<ref name="pmid24842304">{{cite journal| author=Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S et al.| title=Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. | journal=J Hepatol | year= 2014 | volume= 61 | issue= 4 | pages= 891-902 | pmid=24842304 | doi=10.1016/j.jhep.2014.05.023 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24842304  }} </ref>
*[[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)<ref name="pmid3782476">{{cite journal| author=Lackner KJ, Monge JC, Gregg RE, Hoeg JM, Triche TJ, Law SW et al.| title=Analysis of the apolipoprotein B gene and messenger ribonucleic acid in abetalipoproteinemia. | journal=J Clin Invest | year= 1986 | volume= 78 | issue= 6 | pages= 1707-12 | pmid=3782476 | doi=10.1172/JCI112766 | pmc=423946 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3782476  }} </ref>
*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:
{{Family tree/start}}
{{Family tree | | | | | | A01 | | | |A01= Low [[LDL]] C <5th percentile}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | C01 | | | |C01= Rule out secondary causes of low [[LDL]] <br> [[Anemia]] <br> [[Criticial illness]]<br> [[Chronic inflammation]] <br> [[Chronic liver disease]] <br> [[Hyperthyroidism]] <br>[[Infection]] <br> [[Malabsorption]] <br>[[Malignancy]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | | | | | E01 | | | |E01= Consider primary monogenic causes based on [[lipid profile]]}}
{{Family tree | | | | | | |!| | | | | }}
{{Family tree | | |,|-|-|-|^|-|-|.|}}
{{Family tree | | F01 | | | | | F02| |F01= Normal [[Triglycerides]]| F02=Low [[Triglycerides]]}}
{{Family tree | | |!| | | | | | |!| | | | | | }}
{{Family tree | | G01 | | | | | G02 | | |G01= [[Chlyomicron retention disease]] <br> <SMALL>(Confirm with [[gene sequencing]])</SMALL>| G02=Screen the [[lipid profile]] of the patient's parents}}
{{Family tree | | | | | | | | | |!| | | | }}
{{Family tree | | | | | | | |,|-|^|-|-|.| }}
{{Family tree | | | | | | | H01| | |H02|H01=Normal Parental [[Lipid Profile]]|H02=If Parental [[Lipid profile]] <50% of Normal on:<br>*[[LDL]]<br>*[[Total Cholesterol]]<br>*[[Triglycerides]] }}
{{Family tree | | | | | | | |!| | | | |!| }}
{{Family tree | | | | | | |I01| | |I02|I01=Abetalipoproteinemia<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>|I02=[[Familial homozygous hypobetalipoproteinemia]]<br><SMALL>(Confirm with [[gene sequencing]])</SMALL>}}
{{Family tree/end}}


== 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.<ref name="pmid22605972">{{cite journal| author=Terrin G, Tomaiuolo R, Passariello A, Elce A, Amato F, Di Costanzo M et al.| title=Congenital diarrheal disorders: an updated diagnostic approach. | journal=Int J Mol Sci | year= 2012 | volume= 13 | issue= 4 | pages= 4168-85 | pmid=22605972 | doi=10.3390/ijms13044168 | pmc=3344208 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22605972  }} </ref> <ref name="pmid26747865">{{cite journal| author=Overeem AW, Posovszky C, Rings EH, Giepmans BN, van IJzendoorn SC| title=The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. | journal=Dis Model Mech | year= 2016 | volume= 9 | issue= 1 | pages= 1-12 | pmid=26747865 | doi=10.1242/dmm.022269 | pmc=4728335 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26747865  }} </ref>


The table below summarizes the diseases that have similar presentation as abetalipoproteinemia<ref name="pmid22027213">{{cite journal| author=Jung HH, Danek A, Walker RH| title=Neuroacanthocytosis syndromes. | journal=Orphanet J Rare Dis | year= 2011 | volume= 6 | issue=  | pages= 68 | pmid=22027213 | doi=10.1186/1750-1172-6-68 | pmc=3212896 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22027213  }} </ref>:


==References==
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
{{Reflist|2}}
|+
 
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Disease}}
 
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Findings}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[Abetalipoproteinemia]] <br> [[Autosomal recessive]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Mutation]] in MTP gene.
*Presents in with [[steatorrhea]], progressive [[ataxia]], [[dysarthria]], loss of [[proprioceptive]] and [[vibration sense]], diminished deep tendon reflexes, impaired [[visual acuity]] due to [[retinal degeneration]].
*Characteristic labs include absent [[LDL]] C, [[apolipoprotein B]] and [[acanthocytosis]].
*Parents of the affected patient have normal [[lipid]] and [[apolipoprotein B]] levels.
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[Hypobetalipoproteinemia]]<br>[[Autosomal co-dominant]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
* Mutation in APOB gene.
*It difficult to differentiate between homozygous hypobetalipoproteinemia and abetalipoproteinemia as they have similar clinical features and laboratory findings, only differentiating feature is that, parents of affected patient have decreased [[lipid]] levels and [[apolipoprotein B]] in [[homozygous]] [[hypobetalipoproteinemia]].
*[[Heterozygous]] patients have one-fourth to one-third of normal [[LDL]] C, [[apolipoprotein B]] and [[hepatic steatosis]].
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[Fredrich Ataxia]]<br>[[Autosomal recessive]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Mutation in the FXN gene leads to [[triplet repeat expansion]].
*Clinical features include progressive [[ataxia]] and [[dysarthria]], loss of [[proprioception]] and [[vibration sense]], motor weakness, diminished deep tendon reflexes, [[impaired visual aquity]] due to [[optic atrophy]].
*[[MRI]] show widespread white and gray matter damage in the infratentorial and supratentorial areas.<ref name="pmid26688047">{{cite journal| author=Rezende TJ, Silva CB, Yassuda CL, Campos BM, D'Abreu A, Cendes F et al.| title=Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia. | journal=Mov Disord | year= 2016 | volume= 31 | issue= 1 | pages= 70-8 | pmid=26688047 | doi=10.1002/mds.26436 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26688047  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[Vitamin E deficiency]] <br> secondary to [[fat malabsorption]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Seen in patients diagnosed with [[cystic fibrosis]], [[pancreatic insufficiency]], [[crohn's disease]] or [[liver disease]].
* Presents in with [[steatorrhea]], progressive [[ataxia]], loss of [[proprioceptive]] and [[vibration sense]], diminished deep tendon reflexes, impaired [[visual acuity]] due to [[retinal degeneration]].
* Characteristic labs include low [[vitamin E]] and [[acanthocytosis]] with increased [[erythrocyte]] fragility.
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''[[McLeod Syndrome]]<br>[[X-linked recessive]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Mutation in XK gene.
*Usually presents with [[chorea]], [[cognitive impairment]], psychiatric symptoms and diminished deep tendon reflexes.
*Characteristic laboratory finding includes [[acanthocytosis]].<ref name="pmid22027213">{{cite journal| author=Jung HH, Danek A, Walker RH| title=Neuroacanthocytosis syndromes. | journal=Orphanet J Rare Dis | year= 2011 | volume= 6 | issue=  | pages= 68 | pmid=22027213 | doi=10.1186/1750-1172-6-68 | pmc=3212896 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22027213  }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[HARP syndrome]]<br>[[Autosomal recessive]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |
*Mutation in Pantothenate kinase 2.
*HARP: hypoprebetalipoproteinema, [[acanthocytosis]], [[retinitis pigmentosa]], pallidal degeneration.
*Presents with orofacial [[dyskinesia]], [[dystonia]], [[dysarthria]], [[rigidity]] and [[choreoathetosis]] and [[retinal degeneration]].
*Characteristic labs include low prebetalipoprotein, [[acanthocytosis]] and on [[MRI]] pallidal degeneration is noticed.<ref name="pmid12058097">{{cite journal| author=Ching KH, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ| title=HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. | journal=Neurology | year= 2002 | volume= 58 | issue= 11 | pages= 1673-4 | pmid=12058097 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12058097  }} </ref>
|-
|}


==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.
*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|needle aspiration biopsy.]]<ref name="pmid6959555">{{cite journal| author=Muller DP, Lloyd JK| title=Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia. | journal=Ann N Y Acad Sci | year= 1982 | volume= 393 | issue=  | pages= 133-44 | pmid=6959555 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6959555  }} </ref> <ref name="pmid19158321">{{cite journal| author=Iqbal J, Hussain MM| title=Intestinal lipid absorption. | journal=Am J Physiol Endocrinol Metab | year= 2009 | volume= 296 | issue= 6 | pages= E1183-94 | pmid=19158321 | doi=10.1152/ajpendo.90899.2008 | pmc=2692399 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19158321  }} </ref>
* Oral supplementation of [[Vitamin A]] 100–400 IU/kg/day; [[Vitamin D]] 800–1200 IU/day; [[Vitamin K]] 5–35 mg/week.<ref name="pmid848999">{{cite journal| author=Muller DP, Lloyd JK, Bird AC| title=Long-term management of abetalipoproteinaemia. Possible role for vitamin E. | journal=Arch Dis Child | year= 1977 | volume= 52 | issue= 3 | pages= 209-14 | pmid=848999 | doi= | pmc=1546285 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=848999  }} </ref>
*[[Parental]] supplementation of fat soluble vitamins is not preferred due to the risk of [[hepatic steatosis]].<ref name="pmid9745481">{{cite journal| author=Cavicchi M, Crenn P, Beau P, Degott C, Boutron MC, Messing B| title=Severe liver complications associated with long-term parenteral nutrition are dependent on lipid parenteral input. | journal=Transplant Proc | year= 1998 | volume= 30 | issue= 6 | pages= 2547 | pmid=9745481 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9745481  }} </ref>
*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 acid]]s is recommended.


=== Surgery ===
Surgical intervention is not recommended for the management of abetalipoproteinemia.


=== Primary Prevention ===
There are no primary preventive measures available for abetalipoproteinemia.


==Overview==
=== Secondary Prevention ===
Abetalipoproteinemia is a rare autosomal recessive [[genetic disorder]] that interferes with the normal absorption of fat and fat soluble vitamins from food. The syndrome causes the body not to make lipoproteins, including low-density lipoproteins, very-low-density lipoproteins, and chylomicrons. It is an autosomal recessive inherited disorder, which affects both sexes. It predominantly affects males. It is caused by mutations in the genes: apolipoprotein B (APOB) or microsomal triglyceride transfer protein (MTP).
Secondary prevention strategies following abetalipoproteinemia include:
 
*Monitoring [[growth]] in children and to delay neurological complications.<ref name="pmid848999">{{cite journal| author=Muller DP, Lloyd JK, Bird AC| title=Long-term management of abetalipoproteinaemia. Possible role for vitamin E. | journal=Arch Dis Child | year= 1977 | volume= 52 | issue= 3 | pages= 209-14 | pmid=848999 | doi= | pmc=1546285 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=848999  }} </ref>
==Pathophysiology==
*Assessment for [[ataxia]], [[dysarthria]], visual changes every 6 to 12 months.
Abetalipoproteinemia is an  inherited disorder that affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins, which are molecules that consist of proteins combined with cholesterol and particular fats called triglycerides. This leads to a multiple vitamin deficiency, affecting the fat soluble [[Retinol|vitamin A]], [[vitamin D]], [[Tocopherol|vitamin E]], and [[vitamin K]]. However, many of the observed effects are due to vitamin E deficiency in particular.
*As [[vitamin]] levels do not return to normal even after years of treatment, it's recommended to assess for features of deficiency regularly.<ref name="pmid18611256">{{cite journal| author=Zamel R, Khan R, Pollex RL, Hegele RA| title=Abetalipoproteinemia: two case reports and literature review. | journal=Orphanet J Rare Dis | year= 2008 | volume= 3 | issue= | pages= 19 | pmid=18611256 | doi=10.1186/1750-1172-3-19 | pmc=2467409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18611256  }} </ref>
 
Two genes have been identified in which mutations are associated with this disorder: microsomal triglyceride transfer protein (MTTP) and [[apolipoprotein B]] (ApoB).
 
The ''MTTP'' gene provides instructions for making a protein called microsomal triglyceride transfer protein, which is essential for creating beta-lipoproteins. These lipoproteins are necessary for the absorption of fats, cholesterol, and fat-soluble vitamins from the diet and the efficient transport of these substances in the bloodstream. Most of the mutations in this gene lead to the production of an abnormally short microsomal triglyceride transfer protein, which prevents the normal creation of beta-lipoproteins in the body. MTTP associated mutations are inherited in an [[autosomal recessive]] pattern, which means both copies of the gene must be faulty to produce the disease.
 
There is an absence of [[apolipoprotein B]]. On intestinal [[biopsy]], [[vacuole]]s containing lipids are seen in enterocytes.  Since there is no or little assimilation of [[chylomicron]]s, their levels in [[Blood plasma|plasma]] remains low. This disorder may also result in fat accumulation in the liver (hepatic steatosis).  Because the epithelial cells of the bowel lack the ability to place fats into chylomicrons, lipids accumulate at the surface of the cell, crowding the functions that are necessary for proper absorption.
 
==Clinical History, Complications and Prognosis==
This normally results in the affected person being extremely thin, and is normally, if untreated, fatal. It is usually diagnosed in infancy, and sometimes can develop later in life. The signs and symptoms of abetalipoproteinemia appear in the first few months of life. They can include failure to gain weight and grow at the expected rate (failure to thrive); diarrhea; abnormal star-shaped red blood cells ([[acanthocyte|acanthocytosis]]); and fatty, foul-smelling stools ([[steatorrhea]]). Specifically the stool may contain large chunks of fat and or blood.  Other features of this disorder may develop later in childhood and often impair the function of the nervous system. They can include poor muscle coordination, difficulty with balance and movement ([[ataxia]]), and progressive degeneration of the light-sensitive layer (retina) at the back of the eye that can progress to near-blindness. Adults in their thirties or forties may have increasing difficulty with balance and walking. Many of the signs and symptoms of abetalipoproteinemia result from a severe vitamin deficiency, especially vitamin E deficiency which typically results in eye problems with degeneration of the spinocerebellar and dorsal columns tracts.
 
==Signs and Symptoms==
Often symptoms will arise that indicate the body is not absorbing or making the lipoproteins that it needs. These symptoms usually appear en masse, meaning that they happen all together, all the time. These symptoms come as follows:
*Failure to grow in infancy
*Fatty, pale stools
*Frothy stools
*Foul smelling stools
*Protruding abdomen
*[[Mental retardation]]/developmental delay
*[[Dyspraxia]], evident by age ten
*Muscle weakness
*Slurred speech
*[[Scoliosis]] (curvature of the spine)
*Progressive decreased vision
*Balance and coordination problems
 
==Diagnosis==
The inability to absorb fat in the ileum will result in [[steatorrhea]], or fat in the stool. As a result, this can be clinically diagnosed when foul smelling stool is encountered.  Low plasma [[chylomicron]] levels are also characteristic. [[Acanthocytes]] are seen on blood smear.
 
Shown below is an image depicting acanthocytes on blood smear.
 
[[Image:Acanthocytes (abetalipoproteinemia).jpg|thumb|left|Acanthocytes (Abetalipoproteinemia)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>]]
<br clear="left"/>
 
==Treatment==
* Treatment normally consists of rigorous dieting, involving mass amounts of vitamin E. Vitamin E helps the body restore and produce lipoproteins, which people with abetalipoprotenimia usually lack. Vitamin E also helps keep skin and eyes healthy, which studies show that many males whom are affected will have vision problems later on in life. Dyspraxia and muscle weakness is usually combated with psysiotherapy, or [[occupational therapy]].
* Dietary restriction of triglycerides has also been useful.


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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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. doi:10.1172/JCI112766. PMC 423946. PMID 3782476.
  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. doi:10.1146/annurev.nutr.20.1.663. PMID 10940349.
  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. doi:10.1007/s10545-013-9665-4. PMID 24288038.
  11. 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.
  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. doi:10.1161/CIRCGENETICS.115.001106. PMC 4618089. PMID 26224785.
  13. 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. 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). doi:10.1038/ejhg.2012.30. PMC 3400737. PMID 22378282.
  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. doi:10.1038/eye.2001.167. PMID 11767031.
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