Abetalipoproteinemia is a rare disease that is estimated to affect less than 1 in 1 million people in the worldwide population. It can affect people born genetically male and female with equal likelihood. One mutation type of the MTTP gene that causes abetalipoproteinemia is more common in people of Ashkenazi Jewish descent. This is a replacement of a glycine in the protein (one of 20 amino acid types that can make up the protein structure) at position 865 with a stop codon. This means that the gene is not adequately read to the end, leading to an abnormally small and nonfunctional version of the MTTP protein.

The rare disease abetalipoproteinemia is caused by a genetic mutation in the MTTP gene which encodes a protein called microsomal triglyceride transfer protein. There are more than 33 known mutations to this gene that can cause abetalipoproteinemia. This disease can be passed down from parents to their offspring in an autosomal recessive genetic inheritance pattern, meaning that both parents must have a copy of the mutated gene to pass to their offspring (see RareShare Guide on Genetic Inheritance for more information https://rareshare.org/articles/guide ). 

The MTTP gene encodes the genetic information for the body to produce the microsomal triglyceride transfer protein (MTTP) which is responsible for assembling and secreting apoB-lipoproteins in the liver and intestines. They do this by attaching lipids onto apoB proteins to form the very large apolipoprotein biomolecule. Lipoproteins are a combination of two types of biomolecules: lipids and proteins. They act as transporters for lipid, or hydrophobic, molecules that don’t dissolve easily in water or the aqueous environments of the body. Thus, they are necessary to transport fats and fat-soluble vitamins, and without them these nutrients don’t reach locations in the body that need them to function properly. When the MTTP protein isn’t formed properly or isn’t readily available, it reduces the body’s liver and intestines’ ability to absorb and transport fat molecules and fat-soluble vitamins. 

The lack of apo-B lipoproteins caused by this rare disease causes a lack of essential vitamins and nutrients in the body, such as triglycerides, cholesterol, phospholipids, ceramides, vitamins A, E, and K, and reduced apo-A1 liposomes. Deficient lipids in the bloodstream lower the body’s phospholipids that form cell membranes, causing abnormally shaped red blood cells (acanthocytosis) which can lead to anemia. MTTP protein is also expressed in the heart, and abetalipoproteinemia could lead to a build-up of fats in the heart and cause heart problems.

Symptoms of abetalipoproteinemia mostly affect the neurological system, gastrointestinal tract, function of the retinas and eyesight, and red blood cells and blood flow. Loss of fats in the bloodstream causes loss of functions such as neurological deterioration, weakness of the muscles and difficulty walking, abnormally shaped red blood cells (acanthocytosis) resulting in anemia or low blood flow, degeneration of the retina and loss of vision. These symptoms often develop in infants and early childhood development with specific symptoms giving rise to a diagnosis:

Infantile Form

Infants with abetalipoproteinemia will often experience gastrointestinal problems due to poor digestion:

• Pale, bulky, foul-smelling stools (steatorrhea)

• Diarrhea

• Vomiting

• Swollen abdomen

• Lack of weight gain or growing to the expected milestones

Juvenile Form

Between the ages of 2-20 years, children and young adults with abetalipoproteinemia may develop neurological degeneration characterized by loss of ability to coordinate voluntary movements and/or loss of deep tendon reflexes such as the kneecap. Some may have difficulty speaking at this time. Eyesight degeneration in the form of retinitis pigmentosa - where the retina breaks down and causes vision loss - often develops around age 10 due to vitamin deficiency. Most children with abetalipoproteinemia will have normal intellectual capabilities, but may develop at a slower rate and/or experience disability. Other signs of neurological degeneration include tremors, motor tics, and muscle weakness.

Due to a lack of lipids to form phospholipids, the cell membranes of different cell types may be weakened in people with abetalipoproteinemia. This often affects the shape and function of red blood cells, causing acanthocytosis and resulting in less blood circulation and symptoms such as tiredness, weakness, lightheadedness, dizziness, irritability, palpitations, headaches, and pale complexion.

Less common symptoms of abetalipoproteinemia includes skeletal abnormalities such as backward or sideways curvatures of the spine, arched foot or clubfoot, difficulty walking, involuntary eye movements, droopy eyelids or crossed eyes, unequal size of pupils, and development of fatty liver which can cause liver damage if left untreated. 

A diagnosis of abetalipoproteinemia depends on a genetic analysis to determine a mutation of the MTTP gene. This is often done in tandem with testing levels of lipoproteins available in the body, observing the form of red blood cells, and performing an eye exam.

• Measure lipids available in the body: blood tests for triglycerides, cholesterol, and apoB-containing lipoprotein content such as fasting lipid profile or stool study

• Study morphology of red blood cells: complete blood count and blood smear to show acanthocytes (abnormally shaped red blood cells)

• Ophthalmological exam: eye exam to observe the retinas for signs of deterioration

• Hepatic scan or ultrasonogram to assess health of the liver and prevent the development of fatty liver disease

• Magnetic resonance imaging (MRI) of spinocerebellar region to assess development of the spine despite muscle weakness

There is no cure for abetalipoproteinemia, yet there are treatments prescribed to treat specific symptoms that people with this rare disease may be experiencing. It is important that people diagnosed with abetalipoproteinemia receive routine medical examinations, especially for neurological and optical deterioration, to prevent worsening of any symptoms. Some treatment options include:

• Dietary supplements – adding vitamins and reducing dietary fats generally relieve gastrointestinal symptoms, but medium chain fatty acids should be supplemented for long chain fatty acids so that the body can adequately transport shorter lipid molecules

Most people diagnosed with abetalipoproteinemia early in their lifetime are able to receive vitamin and lipid dietary treatment, and avoid fatty foods in general, which reduces their symptoms and lowers the likelihood of neurological, gastrointestinal, optical, and anemia complications. However, it is important to receive regular examinations by doctors to monitor symptoms to prevent damage to the liver and other organ systems. In particular, individuals with abetalipoproteinemia should use caution when taking fat-soluble drugs as they may have trouble delivering them to the area of the body that needs them.

1. https://rarediseases.org/rare-diseases/abetalipoproteinemia/

2.https://medlineplus.gov/genetics/condition/abetalipoproteinemia/#:~:text=Abetalipoproteinemia%20is%20an%20inherited%20disorder,%2C%20E%2C%20and%20K).

3. Junaid SZS, Patel K. Abetalipoproteinemia. [Updated 2022 Aug 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513355/

4. https://rarediseases.info.nih.gov/diseases/5/abetalipoproteinemia

5. https://medlineplus.gov/genetics/gene/mttp/