Abetalipoproteinemia is a rare hereditary condition that impacts the absorption of fats within the intestines and their proper processing by the liver. This inability to effectively absorb fats leads to deficiencies in both lipids and crucial vitamins.
The initial documentation of Abetalipoproteinemia can be attributed to the medical publication by physicians Bassen and Kornzweig in 1950. This condition is alternatively recognized as Bassen-Kornzweig syndrome. At times, the disorder is categorised within the realm of neuroacanthocytosis syndromes. This term encompasses a collection of disorders marked by distinctive spiky or burr-like appearances of red blood cells (referred to as acanthocytosis) alongside various neurological disorders, with a particular focus on movement-related issues.1,2
Those affected by this disorder undergo a gradual decline in neurological function, experience muscle weakness, encounter challenges with mobility, and face blood abnormalities. Among these abnormalities is a condition in which the shape of red blood cells becomes distorted (known as acanthocytosis), resulting in a decrease in circulating red blood cell levels, leading to anaemia. Additionally, individuals with this condition might also encounter retinal degeneration, potentially leading to vision loss, a condition termed retinitis pigmentosa. The inheritance pattern of abetalipoproteinemia follows an autosomal recessive mode, primarily caused by genetic variations (mutations or variants) in the microsomal triglyceride transfer protein (MTTP) gene.1,2
Abetalipoproteinemia (ABL) is a rare autosomal recessive condition characterised by diminished or lacking levels of plasma cholesterol, low-density lipoproteins (LDLs), and very low-density lipoproteins (VLDLs). Distinctive indicators for the condition encompass challenges in fat absorption, spinocerebellar degeneration, the presence of acanthocyte red blood cells, and the development of retinitis pigmentosa.
The therapeutic goal is to halt neurological symptoms and address the complications arising from deficiencies in affected individuals.1
Causes and Genetics
Autosomal Recessive Inheritance and Role of Microsomal Triglyceride Transfer Protein (MTTP) Gene
Abetalipoproteinemia arises due to a homozygous autosomal recessive alteration within the so-called MTTP gene. “Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes. “Recessive” means that two copies of the mutated gene (one from each parent) are required to cause the disorder. Over 33 distinct mutations contributing to the manifestation of this condition have been recognized. The MTTP gene encodes microsomal triglyceride protein (MTP), which orchestrates the assembly and transportation of intracellular chylomicrons (particles which transport dietary lipids from the intestines to other locations in the body) in the intestinal mucosa and hepatocytes. The majority of symptoms stem from pronounced scarcities in fats and fat-soluble vitamins, particularly vitamin E. Typically evident in infants, the disorder's onset is marked by failure to thrive, steatorrhea (fatty stools), and abdominal distension, culminating in spinocerebellar degeneration and retinitis pigmentosa causing visual issues.1,3
Mechanism and Effects
Abetalipoproteinemia is brought about by alterations (mutations or changes) in the MTTP gene and is inherited in a recessive genetic pattern. Genetic traits come from two alleles, one from each parent. An allele is a version of a gene.
Recessive genetic issues happen when someone gets two abnormal alleles for the same trait, one from each parent. If a person gets one normal allele and one allele for the disease, they become a carrier but usually don't show symptoms. If both parents are carriers, the chance of having an affected child is 25%. The chance of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to get normal genes from both parents and not have the trait is 25%.
Everyone carries some abnormal genes. If parents are closely related, they have a higher chance than unrelated parents of both having the same changed gene. Some people with abetalipoproteinemia have parents who are blood relatives. This raises the risk of having kids with a recessive genetic disorder.
The MTTP gene provides instructions to make a protein called microsomal triglyceride transfer protein (MTP). This protein helps put together and release lipoproteins in the liver and intestines. Changes in the MTTP gene lead to lower levels of working MTP. This makes it hard for the liver and intestines to make and release apoB-containing lipoproteins. As a result, the body can't properly take in and move fats and fat-soluble vitamins. So, the lack of these apoB-containing lipoproteins in the blood leads to symptoms and vitamin shortages.1,4
Recent research found that MTP also helps with proteins called CD1, which are part of immune cells that deal with lipids. MTP also affects fat breakdown in fat tissue by stopping a protein called adipose triglyceride lipase. There's still more to learn about MTP's complete roles and how it causes abetalipoproteinemia.
Also, studies show MTP is present in the heart tissue and helps move lipids out of it. Low MTP levels might lead to fat buildup in the heart and affect how it works.1
Diagnosis and Medical Evaluation
A diagnosis of abetalipoproteinemia relies on recognizing typical symptoms, studying the patient's medical history, conducting a thorough clinical assessment, and performing specific tests. These tests include assessments of lipid levels (triglycerides and cholesterol) and apoB-containing lipoproteins in the blood plasma, examining the structure of red blood cells and an eye examination.
Blood tests will show lower levels of lipids like cholesterol, triglycerides, and vitamins A, E, and K. ApoB-containing lipoproteins such as chylomicrons or very low-density lipoproteins won't be found in the blood plasma. Blood tests can also reveal malformed red blood cells (acanthocytosis).
A comprehensive examination of neurological function, eye health, endoscopy, and a liver ultrasound might be done to assess potentially related symptoms. To confirm the diagnosis, genetic testing at the molecular level can be conducted to identify harmful changes in the MTTP gene.1
Treatment and Management
The approach to treating abetalipoproteinemia focuses on addressing the specific symptoms observed in each individual. Treatment often involves a collaborative effort among various specialists. Neurologists, hepatologists (liver specialists), ophthalmologists (eye specialists), lipidologists (experts in fats), gastroenterologists, nutritionists, and other healthcare professionals may work together to create a comprehensive and systematic treatment plan for affected individuals. Regular monitoring, occurring every 6-12 months, is essential. Routine neurological and eye examinations help track potential deterioration in these areas. Yearly measurements of amino transaminases in the blood assess any liver damage, while hepatic ultrasound detects fatty liver presence. Echocardiography (ECG), every three years, ensures proper heart function.
Many individuals respond positively to dietary adjustments, specifically a diet low in long-chain saturated fatty acids. Reducing dietary fat intake often alleviates gastrointestinal symptoms. Frequent dietary counselling is crucial, especially for infants whose diets may be supplemented with medium-chain fatty acids, promoting normal growth.
Administering high doses of fat-soluble vitamins (A, E, K) orally helps prevent or improve the symptoms linked to abetalipoproteinemia. Vitamin E and A supplementation, for instance, can deter neurological and retinal complications. Vitamin D supplementation aids some bone growth-related symptoms. Monitoring blood vitamin levels during follow-ups is important, as they don't always reflect ingested amounts. Dosing should adjust based on blood panels, and neurological and eye exams. Despite measurement challenges, vitamin E therapy should continue.
Prognosis varies widely among patients. Early detection, treatment, and vitamin supplementation can mitigate neurological and eye deficiencies. Careful monitoring is necessary if they receive fat-soluble drug treatments unrelated to abetalipoproteinemia, as these processes might be impacted. Additional treatment focuses on symptom management and support.
For families with children having abetalipoproteinemia, genetic counselling is advisable.1
Prognosis and Lifestyle Considerations
Prognostic factors are as follows:
- Age of Diagnosis
- Early commencement of therapy involving a low-fat diet and vitamin supplementation
- Nature of MTP mutation and APOE genotype in relation to the long-term outlook of individuals affected by abetalipoproteinemia1
Research and Future Directions
Gene therapy has been explored as an additional strategy for addressing abetalipoproteinemia in individuals. This technique involves introducing a healthy gene to generate the functional protein, thereby impeding the advancement of the particular disease. Nonetheless, there are significant technical challenges that need to be addressed before gene therapy can be considered a practical alternative method.1
In summary, Abetalipoproteinemia is a somewhat rare hereditary condition which affects the intestinal absorption of fats in the intestine, as well as the processing of fats which is normally done in the liver. This will lead to deficiency in lipids as well as vitamins, which will further lead to potential neurological deterioration with muscle weakness, blood abnormalities and visual disturbances which can lead to loss of vision.
The prognosis of people affected by the disease is variable, with early detection and regular monitoring of affected individuals being crucial, as well as genetic counselling for families of children with abetalipoproteinemia.
- Junaid SZS, Patel K. Abetalipoproteinemia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Aug 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK513355/
- Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis [Internet]. 2008 Dec [cited 2023 Nov 17];3(1):19. Available from: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-19
- Wang LR, McIntyre AD, Hegele RA. Complex genetic architecture in severe hypobetalipoproteinemia. Lipids Health Dis [Internet]. 2018 Dec [cited 2023 Nov 17];17(1):48. Available from: https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0680-1
- Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014 Oct;61(4):891–902. Available from: https://pubmed.ncbi.nlm.nih.gov/24842304/