Question

1. Why do abetalipoproteinemia (ABL), chylomicron retention disease, and homozygous hypobetalipoproteinemia present so similarly? How would one differentiate between them?
2. Acanthocytosis is associated with ABL, but not with chylomicron retention disease. Explain.
3. Hypobetalipoproteinemia presents clinically only in the homozygous state. Why does it sometimes present similar to ABL with absent plasma apoB lipoproteins and at other times as much milder phenotype?

Answer 1

PART 1

• Abetalipoproteinemia (ABL) - is a disorder that interferes with the normal absorption of fat and fat soluble vitamins from food.
• Chylomicron retension disease - Also known as Anderson disease. it is a disorder of fat absorption. It is associated with SAR1B gene. Mutations in SAR1B prevent the release of chylomicrons in the circulation which leads to nutritional and developmental problems. It is a rare autosomal recessive disorder. Without functional chylomicrons certain fat-soluble vitamins such as vitamin D and vitamin E cannot be absorbed. Chylomicrons have a crucial role in fat absorption and transport, thus deficiency in chylomicron functioning reduces available levels of dietary fats and fat-soluble vitamins.
• Homozygous hypobetalipoproteinemia - Also known as Familial hypobetalipoproteinemia. it is a disorder that impairs the body's ability to absorb and transport fats. This condition is characterized by low levels of a fat-like substance called cholesterol in the blood. Many individuals with hypobetalipoproteinemia develop an abnormal buildup of fats in the liver called fatty liver. In more severely affected individuals, fatty liver may progress to chronic liver disease (cirrhosis). Individuals with severe hypobetalipoproteinemia have greater difficulty absorbing fats as well as fat-soluble vitamins such as vitamin E and vitamin A. This difficulty in fat absorption leads to excess fat in the feaces (steatorrhea).
• Chylomicron retention (Anderson) disease is similar to homozygous hypobetalipoproteinemia and abetalipoproteinemia in its gastrointestinal manifestations (whose symptoms are nonspecific and range from mild to life-threatening) and impact on growth, although acanthocytosis (Acanthocytosis is a red cell phenotype associated with various underlying conditions. Acanthocytes or spur cells, are spiculated red cells with a few projections of varying size and surface distribution) is usually absent and neurologic and ocular abnormalities are much less severe.
• The above three disease are similar in that they affect the body's ability to absorb fat and fat soluble vitamins from diet.
• Another major similarity between these diseases are that they are Autosomal disorders. To have an autosomal recessive disorder, you inherit two mutated genes, one from each parent. These disorders are usually passed on by two carriers. Their health is rarely affected, but they have one mutated gene (recessive gene) and one normal gene (dominant gene) for the condition. Eg: Cystic fibrosis, Tay-Sach's disease etc.  

PART 2

• Acanthocyte refers to a form of red blood cell that has a spiked cell membrane, due to abnormal thorny projections.
• Acanthocytes arise from either alterations in membrane lipids or structural proteins. Alterations in membrane lipids are seen in abetalipoproteinemia and liver dysfunction.

• In liver dysfunction, apolipoprotein A-II deficient lipoprotein accumulates in plasma causing increased cholesterol in RBCs. This causes abnormalities of membrane of RBC causing remodeling in spleen and formation of acanthocytes.In abetalipoproteinemia, there is deficiency of lipids and vitamin E causing abnormal morphology of RBCs.

• Acanthocytes can be seen in advanced liver disease, rare vitamin E genetic deficiency or neurodegenerative syndromes or homozygous HB. In Chylomicron retention disesase (CRD), acanthocytosis is rare, and sometimes transient. It is dependent on the vitamin E level which is a key to red cell membrane integrity. Therefore, the presence of acanthocytosis is hardly compatible with CRD.

PART 3

• Hypobetalipoproteinemia presents clinically only in the homozygous state - Homozygous is a word that refers to a particular gene that has identical alleles on both homologous chromosomes. It is referred to by two capital letters (XX) for a dominant trait, and two lowercase letters (xx) for a recessive trait.
• This condition is inherited in an autosomal codominant pattern. Codominance means that copies of the gene from both parents are active (expressed), and both copies influence the genetic trait. In FHBL, a change in one copy of the APOB gene in each cell can cause the condition, but changes in both copies of the gene cause more severe health problems.

PART 4

• Hypobetalipoproteinemia is sometimes present similar to ABL with absent plasma apoB lipoproteins and at other times as much milder phenotype.
• Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder that is highly variable in its expression. Severe cases are nearly indistinguishable from individuals with abetalipoproteinemia.
• Symptoms can include steatorrhea, ataxia, retinitis pigmentosa, and neuropathy. Acanthocytosis occurs in some cases as well.
• Treatment of individuals with FHBL is similar to treatment for individuals with abetalipoproteinemia. FHBL is caused by mutations in the APOB, PCSK9, or ANGPTL3 genes and is inherited as an autosomal dominant trait. Contrary to abetalipoproteinemia, the presence of only one altered allele is sufficient to display symptoms of the disease.