Abetalipoproteinemia
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
It is a disease with autosomal recessive inheritance, affecting the etc. Abetalipoproteinemia and hypobetalipoproteinemia together are reffered to as familial hypolipoproteinemia. These are a set of diseases which specifically have low LDL C levels.
Historical Perspective
- The first clinical association of peripheral blood acanthocytosis with atypical retinitis pigmentosa and ataxia was first reported by Bassen and Kornzweig in 1950.[1]
- In 1958, Jampel and Falls observed low serum cholesterol values in affected individuals.[2]
- In 1960, Salt noticed the absence of serum beta-lipoprotein in a patient with the syndrome. Consequently the name of the disease was changed to ABL .Eventually, the fundamental biochemical defect was determined to be a complete absence of plasma apolipoprotein (apo) B-containing lipoproteins, namely chylomicrons, very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL).[2]
- In 1986, the APOB gene, its mRNA and the apo B content of the hepatocytes were found to be normal in ABL patients, suggesting that defective post-translational processing and secretion of apo B was the cause of ABL.[3]
- In 1992, a deficiency of microsomal triglyceride transfer protein (MTP) activity was suggested to be the proximal cause of ABL.[4]
- In 1993, the region on chromosome 4q22-24 that encodes the large subunit of MTP was cloned and sequenced, and human MTP mutations in ABL patients were reported.[5]
Pathophysiology
Genetics
- Autosomal Recessive Inheritance.[6].[7]
- Mutation of MTTP gene which codes for the Microsomal Trigyceride transfer Protien, MTP.[4]
- MTTP gene mutation occurs on chromosome 4q 22-24[5], 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.[8]
- Patients with heterozygous expression have normal lipoprotein levels indicating that both the alleles of the gene coding for MTTP must be defective.
Pathogenesis
- The defect in the MTP causes accumalation of lipid in the intestine leading to Steatorrhea and malabsorption of fat soluble vitamins.
- Accumalation of lipid in the liver causes hepatic steatosis.
- The result of this excessive accumalation causes very low LDL C and VLDL.
- Vitamin E deficiency features are more prominent because the absorption and transport of vitamin E is parallel to the total body lipid levels due to its hydrophobic nature. Spinocerebellar and posterior columns are affected as only minimal amount of vitamin E was transported in HDL C resulting in neurological symptoms.[9]
Diagnosis
Clinical Features
- Patients present in infancy with symptoms of chronic diaarhea, steatorrhea, failure to thrive.
- The most serious symptoms are neurological due to demyelination, which begins in the first or second decade of life and include progressive ataxia and peripheral neuropathy.
- Less common symptoms due to long term fat soluble vitamin deficiency are:
- Easy bruising
- Osteomalacia
- Reduced vision
Physical Examination
Specific physical exam findings include as follows:
- Reduced Visual Acuity and degenerative changes in the retina secondary to Vitamin A deficiency.
- Hepatomegaly
- Neurological:
- Truncal Ataxia due to the effect on spinocerebellar tracts.
- 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.
- Reflexes can be either present or diminished.
Labs
Characteristic labs include :
- Low Triglyceride and total cholesterol levels.
- Absent Beta-lipoprotien on electrophoresis and genetic testing.
- Peripheral Smear shows 50 to 90% of acanthocytes.
- Nerve conduction studies show reduced or absent action potential.
- Very low or Undetectable vitamin E levels.
- Elevated LFT's due to hepatic steatosis.
Differential Diagnosis
- Hypobetalipoproteinemia: Clinical Features, peripheral smear and lipid analysis are similar.
- Severe Vitamin E deficiency: Neurological Symptoms improve significantly with supplementation of Vitamin E.
- Friedrich Ataxia.
Treatment
- 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.
- Fat soluble vitamins( A, K and D) supplementation.
- Diet modification to control gastrointestinal symptoms.
Hypobetalipoproteinemia
It shares similar clinical and lab features with abetalipoproteinemia.
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
- Based on a Study which involved genetic analysis in 2010, showed
- Patients commonly have low levels of plasma ApoB and LDL cholesterol.
References
- ↑ BASSEN FA, KORNZWEIG AL (1950). "Malformation of the erythrocytes in a case of atypical retinitis pigmentosa". Blood. 5 (4): 381–87. PMID 15411425.
- ↑ 2.0 2.1 Sturman RM (1968). "The Bassen-Kornzweig syndrome: 18 years in evolution". J Mt Sinai Hosp N Y. 35 (5): 489–517. PMID 5245476.
- ↑ 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.
- ↑ 4.0 4.1 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.
- ↑ 5.0 5.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
Overview
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).
Pathophysiology
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 vitamin A, vitamin D, vitamin E, and vitamin K. However, many of the observed effects are due to vitamin E deficiency in particular.
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, vacuoles containing lipids are seen in enterocytes. Since there is no or little assimilation of chylomicrons, their levels in 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 (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.
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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.