Abetalipoproteinemia is a rare disorder which affects the absorption of fat by the intestine and mobilisation by the liver. If fats are not absorbed properly, it results in the deficiency of various lipids and essential vitamins. Patients who are affected by this disease suffer through neurological deterioration, muscle weakness, and blood abnormalitie,s including conditions such as acanthocytosis, which results in anaemia.¹ The signs and symptoms of this condition include main effects on the gastrointestinal system, eyes, nervous system and blood. 

This is a growing condition which has more than 100 cases which have been described worldwide.² It is important to understand the pathophysiology of abetaliproteinemia in order to develop the right approaches for treatment and efficient management of the condition. This article provides an overview of the condition along with its causes and symptoms and provides a deep insight into the different management and treatment methods for patients. 

Genetic basis 

This condition is due to inheriting an autosomal recessive pattern. This means that both the copies of the gene in each of the cells have mutations. ² This means that the parents of the person with the inherited gene have a copy of the mutated gene each, however, they do not show any signs or symptoms associated with the condition as they are simply carrying the gene.

A biallelic pathogenic mutation in the MTTP has been reported as the cause for abetalipoproteinemia. This gene allows the making of the protein called microsomal triglyceride transfer protein, which is needed to create molecules like beta lipoproteins in the liver. These lipoproteins are responsible for carrying fats, cholesterol and fat-soluble vitamins within the body, and healthy levels of these within the body contribute to the maintenance of the body's cells and tissues. 

Mutations in the MTTP gene lead to the production of microsomal triglyceride transfer protein, which does not function normally and, hence, is not able to help to form beta-lipoproteins. If there is a lack of these lipoproteins, then there is malabsorption of dietary fats and fat-soluble vitamins from the digestive tract to the bloodstream.² Thus, due to this, people with abetalipoproteinemia develop nutritional deficiencies which impact their overall health. 

Molecular and cellular mechanisms

Microsomal triglyceride transfer protein (MTP) belongs to a group of proteins which transfer lipids in between membranes. MTP is an 894 amino acid protein, and it forms a heterodimer.³ This is formed by PDI (protein disulfide isomerase), the two subunits are held together by covalent interactions. The loss of function mutations in MTP causes abetalipoproteinemia. 

The microsomal triglyceride protein binds lipids individually between membranes and, hence, leads to the synthesis of chylomicrons and VLDL. After these are assembled, they are transferred to the Golgi apparatus. MTP also transfers lipids to antigen-presenting cells or natural killer T cells, hence, mediating autoimmune disorders.³

Apolipoprotein B helps to transport hydrophobic lipids and are assembled in enterocytes and hepatocytes, they are responsible for transporting endogenous and dietary fat. This assembly occurs in the ER, and this process is dependent on the lipid resynthesis in the ER and on MTTP. Thus, MTTP is responsible for transferring phospholipids and triglycerols to nascent apoB. This is important in order to assemble lipoproteins. The impaired assembly and secretion of lipoproteins lead to various disorders.⁴

Lipoprotein deficiency

The beta lipoproteins are lipoproteins of different molecular weights with the two most prominent subtypes: apo-beta-100, which is in hepatocytes and forms components of VLDL and LDL, and apo-beta-48, which forms chylomicrons in enterocytes. The apo-beta-100 subtype consists of the receptor binding domain, and the lipoproteins are responsible for the uptake of lipids by binding to different receptors. 

Hence, when there is a lack of VLDLs and LDLs, there are consequently low levels of plasma cholesterol and triglycerides. However, since there is an increase in the cholesterol capacity, the level of HDLs delivered to cells remains virtually the same.⁵ Thus, there is a significant difference in the blood lipid levels and lipid metabolism for individuals with and without abetalipoproteinemia, which is based on the transfer of lipids to apolipoproteins and 

Clinical manifestations

The initial signs and symptoms of this condition have been noticed during infancy due to the malabsorption of fat. The characteristics during infancy particularly include growth and development issues. This could include failing to gain weight and grow at the expected rate. 

The gastrointestinal clinical manifestations include: 

• Diarrhoea and vomiting
• Steatorrhea 

Hematologic manifestations include:

• Acanthocytosis (irregular spiculated erythrocytes)
• Anaemia 
• Reticulocytosis
• Hemolysis with hyperbilirubinemia 

The malabsorption of fat-soluble vitamins. This results in an increase in INR, which is the internalised normalised ratio. 

The ophthalmologic manifestations include:

• Acquired atypical pigmentation of the retina (ophthalmologic manifestations)
• Loss of night or colour vision
• Spinocerebellar ataxia and myopathy
• Some rare manifestations include ptosis, ophthalmoplegia, and corneal ulcers, with the first two being especially due to vitamin E deficiency

Neuromuscular manifestations develop in the first or second decade of life of abetalipoproteinemia secondary to the deficiency of vitamin E. These manifestations include:

• Progressive muscle loss of deep tendon reflexes
• Muscle weakness
• Dysarthria
• Friedrich’s-like ataxia 

Other rare manifestations include:

• Cardiomegaly could occur after several years 
• Subclinical and over hyperthyroidism
• Hepatomegaly, which is an enlargement of the liver⁶

The complications with abetalipoproteinemia could be developed in the long term, and these include:

• Malnutrition and systemic effects due to malabsorption of fat in the body
• Long-term neurological complications occurring due to a severe lack of vitamin E
• Retinitis pigmentosa (vision loss)⁷

Diagnosis

The diagnosis of abetalipoproteinemia is based on lipid analysis, which is done after 12 hours of fasting and is carried on in order to measure the serum levels of LDL, triglycerides and apolipoprotein B after oral lipids. The steatorrhoea is misidentified after the oral lipid intake. 

Liposoluble vitamins like vitamin A, E, and K are measured using blood smears for testing for acanthocytosis. A neurological examination can take place as well as hepatic ultrasound and eye examination. Furthermore, the diagnosis is confirmed after identifying mutations of the MTTP gene or APOB gene. ⁸ 

The diagnosis of abetalipoproteinemia is “established in a proband with absent or extremely low LDL-cholesterol, triglyceride and apolipoprotein (apo) B levels”.³ It also involves biallelic pathogenic variants in MTTP, and this is done by conducting molecular gene testing.  

Management and treatment 

In order to treat patients with abetalipoproteinemia, the following procedures can be done. The dietary modifications include;

• Reducing the fat intake in order to prevent steatorrhea by restricting the total fat intake to less than 30% of the total energy intake. 
• Taking adequate calories to promote growth. It is important to note that fat malabsorption could also lead to the malabsorption of other nutrients such as carbohydrates, proteins, etc. 

Fatty acid supplementation can be taken orally. In terms of managing complications, such as neurological complications in particular, huge doses of vitamin E (100 mg/kg/day) help to prevent symptoms from occurring or stop them from getting worse. Similarly, high-dose supplementation of vitamin A can also be done along with supplementation of B, K, B12, iron and folate to prevent malnutrition. Furthermore, for neurological complications or other complications, a multidisciplinary approach should be done.⁹

Prognosis

Since this disease affects the breaking down of fats, prognosis involves the use of high-dose fat-soluble vitamin supplementation, which has helped individuals affected with abetalipoproteinemia survive for longer than a third decade of life. The severity only increases due to neuromyopathy and respiratory failure. Due to the usage of high-dose oral fat-soluble vitamins, there has been longevity in life reported along with lessened severity of symptoms.³

It should be noted that an early diagnosis and use of high-dose vitamin supplementation would help prevent complications in the long term and help to manage the condition appropriately. Furthermore, regular monitoring and dietary modifications, as discussed above, are all essential factors, despite the challenges in following up and adhering to these intervention methods.¹⁰

Summary 

Thus, the conditional abetalipoproteinemia is a rare autosomal recessive disorder which is caused by a mutation in the MTTP gene and leads to impaired assembly and secretion of apo-B containing lipoproteins. The article covers a range of symptoms, diagnosis and management and treatment methods for this condition.  

In terms of future direction for research for treatment for abetalipoproteinemia, gene therapy has been seen as an alternative therapy used for treatment. In this, a normal gene is used to produce the active protein to prevent the progression of the condition or any further complications.¹  Furthermore, research into new treatments and therapies can be targeted at developing treatments for molecular mechanisms of the disease, and the treatment plans can also be made specific to different individuals. Early detection and appropriate management of the condition are the keys to preventing complications. Further research, public awareness and appropriate management of the disease is the most efficient path to develop new treatments and improve the lives of individuals with abetalipoproteinemia.