Treatment And Management Strategies For Abetalipoproteinemia

Introduction

Definition of Abetalipoproteinemia 

Abetalipoproteinemia (ABL) also known as Bassen–Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism due to mutations in the microsomal triglyceride transfer protein (MTP)-encoding gene located on chromosome 4q23.¹

The disease is also referred to as synonymous with the following

• Low-density lipoprotein deficiency
• Microsomal triglyceride transfer protein deficiency
• MTP deficiency
• Familial hypobetalipoproteinemia due to secretion defect 1 (FHBL-SD1).⁴

Pathophysiology 

ABL is an autosomal recessive disorder caused by mutations in both alleles of the microsomal triglyceride transfer protein (MTTP) gene. The protein is found in the lumen of the endoplasmic reticulum in hepatocytes and intestinal epithelial cells. It is essential for the formation of very low-density lipoproteins (VLDLs) and chylomicrons (CMs) by transferring triglyceride (TG) and cholesterol ester to apoB. A lack of MTTP abolishes the secretion of apoB-containing lipoproteins, which results in the malabsorption of dietary fat and fat-soluble vitamins and the accumulation of intracellular lipids in hepatocytes and intestinal epithelial cells.²

Importance of Treatment and Management

Sincemicrosomal triglyceride transfer protein (MTTP) is necessary for lipoprotein assembly, the mutation impairs the synthesis of apoB peptide of low-density lipoprotein and very low-density lipoprotein; this leads to impaired fat absorption and in turn, vitamin E deficiency. If this condition is not treated properly, it can trigger vitamin deficiencies causing long-term effects on health.³

Diagnosis of Abetalipoproteinemia

Abetalipoproteinemia is diagnosed based upon the presence of the following

• Identification of symptoms
• Patient history
• Clinical evaluation 
• Determining the morphology of red blood cells 
• Ophthalmological exam.
• Endoscopy and a liver (hepatic) ultrasound 
• Blood tests to measure levels of triglyceride, cholesterol and apo B-containing lipoproteins in the plasma
• Molecular genetic testing⁴

Signs and symptoms

Clinical Symptoms 

Gastrointestinal Symptoms 

The disease is characterized by the presence of symptoms relating to the gastrointestinal tract due to poor fat absorption. These symptoms include:

• Pale and foul-smelling stools (steatorrhea)
• Diarrhoea
• Vomiting 
• Swelling of the abdomen
• Affected infants experience low weight 

Neurological Symptoms 

Neurological symptoms usually occur between the ages of 2 and 20 years and include:

• Ataxia 
• Loss of deep tendon reflexes 
• Difficulty speaking (dysarthria)
• Tremors
• Motor tics and 
• muscle weakness
• Developmental delays or intellectual disability 
• In some people, peripheral neuropathy may occur which can cause weakness of the muscles of the arms and legs and abnormal sensations such as tingling and burning sensation

Ophthalmological Symptoms

Ophthalmological symptoms are due to the progressive degeneration of the retina.

Symptoms include:

• Rapid, involuntary eye movements (nystagmus)
• Droopy upper eyelid
• unequal size of the pupils (anisocoria) and 
• weakness of muscles that control eye movements (ophthalmoplegia)^{2 4}

Hematological abnormalities

Blood abnormalities include 

• Acanthocytosis 
• Low erythrocyte sedimentation rate (ESR)
• Anemia
• Hemolysis
• Reticulocytosis
• Hyperbilirubinemia, and 
• Elevation of prothrombin time
• Elevation of International Normalized Ratio (INR)
• Fatty liver due to impaired secretion of VLDL²

Treatment Strategies

Dietary Modifications 

• Low-Fat Diet 
• High-Calorie Diet 

Vitamin Supplementation 

• Vitamin E 
• Vitamin A 
• Vitamin K 
• Vitamin D 

Enzyme Replacement Therapy 

Treatment and Management

Following treatment strategies are recommended for a patient suffering from abetalipoproteinemia.

Restriction of fat intake

Restriction in the intake of fat is necessary to prevent steatorrhea. Ideally, it is recommended that the total fat intake should be less than 30% of the total energy intake, or simply 15 to 20 g per day. The guidelines suggest a fat intake of even less than 5 g per day in children.⁵ Increased fat in the stool may cause oxalate urolithiasis This might be prevented by providing supplementary dietary calcium, fluid intake, and reducing dietary oxalate.

Adequate calorie intake 

Adequate calorie intake is crucial to prevent growth retardation. It's important to recognize that fat malabsorption can result in the malabsorption of carbohydrates, proteins, and other nutrients. A fat-restricted diet can help mitigate this secondary malabsorption.

Medium-chain triglyceride (MCT) administration 

This strategy helps in correcting malnutrition, particularly in infants. MCTs are not absorbed and transported in the circulation by chylomicrons but by albumin. Administration of medium-chain triglycerides can cause hepatic fibrosis so liver enzymes should be monitored in infants who are administered MCTs. it is recommended to avoid its long-term administration.

Oral supplementation of essential fatty acid 

The daily requirement for essential fatty acids is up to 1 teaspoon per day of oil consisting of polyunsaturated fatty acids (e.g., soybean or olive oil) is recommended.⁶

High-dose oral vitamin E supplementation 

5,000-10,000 mg/day.²

Vitamin E delays or prevents neurological complications. Serum vitamin E levels do not correlate with tissue vitamin E levels. Better methods and advanced techniques of monitoring tissue vitamin E concentrations are needed. Vitamin E may be administered intravenously and intramuscularly. However, oral supplementation is preferred due to the ease of life-long supplementation and no apparent toxicity. Since the fatty liver and other complications accompany other routes of supplementation. The side effects of administering large doses of vitamin E should be kept in mind as too much absorption of vitamin E may cause vitamin K deficiency. 

High-dose oral vitamin A supplementation 

100-400 IU/kg/day and vitamin E supplementation can prevent ophthalmological complications.⁷

Supplementation of vitamin D 

Ideally, 800-1,200 IU/day should be administered to the patient suffering from abetalipoproteinemia in cases of vitamin D deficiency.⁶

Supplementation of vitamin K 

The guidelines recommend that 5-35 mg/week should be administered in cases of vitamin K deficiency with hypothrombinemia and prolonged PT-INR. Supplementation of vitamin K will normalize these blood tests.⁶

Supplementation of iron, folate, or vitamin B12 

Iron, folic acid and vitamin B12 are necessary in the case of anaemia as they help in the proliferation and maturation of red blood cells thus diminishing the symptoms arising due to anaemia.

Multidisciplinary care for neurological complications 

Multidisciplinary care necessitates collaboration among neurologists, physiatrists, physical therapists, occupational therapists, and speech therapists.

Particular caution should be taken to avoid vitamin A toxicity which can be seen even in those who have a normal plasma vitamin A concentration. To avoid toxicity, it is recommended that vitamin A levels should be lower than the normal limit and the dose of vitamin A supplementation should be monitored regularly by monitoring blood concentrations of vitamin A and β-carotene.  A 50% reduction in dose is necessary for pregnant women or those who are planning to conceive to avoid vitamin A toxicity. The supplementation of vitamin A should not be discontinued in pregnancy as its deficiency could cause lethal complications in pregnant women.²

Monitoring and follow-up

The recommended assessments for ABL patients include 

• Evaluation of growth at every visit
• Annual blood analysis including 
• Lipid profile (Total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apoB, apoA-I)
• Liver function tests (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, bilirubin, alkaline phosphatase, albumin)
• Fat-soluble vitamins (Vitamin A, β-carotene, vitamin D, vitamin E, vitamin K)
• Micronutrients (vitamin B12, iron, folate)
• Complete blood count
• PT-INR, reticulocyte count
• ESR
• Calcium, phosphate, uric acid, and thyroid-stimulating hormone (TSH)
• Ophthalmological and neurological evaluation every 6-12 months
• Hepatic ultrasonography every 3 years²

Challenges in Treatment and Management

• Adherence to Dietary and Supplement Regimens 
• Monitoring and Adjusting Treatment 
• Addressing Long-term Complications

Summary

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene, leading to impaired fat absorption and vitamin deficiencies. Diagnosis involves identifying symptoms, patient history, clinical evaluation, and genetic testing. Symptoms include gastrointestinal issues, neurological complications, ophthalmological problems, and haematological abnormalities. Treatment focuses on dietary modifications, including a low-fat and high-calorie diet, and supplementation of vitamins E, A, D, and K. Medium-chain triglycerides and essential fatty acids may also be administered. Multidisciplinary care is essential for managing neurological complications. Regular monitoring of growth, blood tests, and evaluations are recommended to manage the disease effectively.

Frequently Asked Questions (FAQs)

What is Abetalipoproteinemia (ABL)?

Abetalipoproteinemia (ABL) also known as Bassen–Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism due to mutations in the microsomal triglyceride transfer protein (MTP)-encoding gene

How is Abetalipoproteinemia diagnosed?

Diagnosis is based on identifying symptoms, patient history, clinical evaluation, red blood cell morphology, ophthalmological exams, endoscopy, liver ultrasound, blood tests for triglycerides, cholesterol, and apoB-containing lipoproteins, and molecular genetic testing.

What are the main symptoms of Abetalipoproteinemia?

Symptoms include gastrointestinal issues (steatorrhea, diarrhoea, vomiting), neurological problems (ataxia, dysarthria, muscle weakness), ophthalmological issues (nystagmus, anisocoria), and haematological abnormalities (acanthocytosis, anaemia).