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Abetalipoproteinaemia
This genetic disorder, present from birth, leads to a deficiency in fats and vitamins, primarily affecting the digestive system and nervous system. It can cause problems with growth, vision, balance, and muscle coordination.
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Overview
Abetalipoproteinaemia is a very rare inherited condition that disrupts the body's ability to properly absorb and transport certain fats and fat-soluble vitamins from food. Individuals with this condition cannot produce specific lipoproteins, which are particles essential for carrying fats around the bloodstream. This leads to a build-up of fats within the intestinal cells and a severe deficiency of fats in the blood, particularly triglycerides and cholesterol [PMID:11340156].
Because fat-soluble vitamins (A, D, E, and K) rely on fat absorption for their uptake, people with abetalipoproteinaemia often experience severe deficiencies in these vitamins. These deficiencies can lead to a range of health problems affecting various body systems, including the digestive, neurological, and visual systems. The condition is present from birth, although symptoms may develop gradually over time.
Symptoms & clinical features
Symptoms of abetalipoproteinaemia typically begin in infancy or early childhood. Digestive issues are often among the first signs and can include oily, foul-smelling stools (steatorrhoea), abdominal bloating, and failure to gain weight and grow at the expected rate (failure to thrive) [PMID:33671077]. These problems stem from the inability to absorb dietary fats correctly.
Over time, neurological symptoms usually emerge due to chronic vitamin deficiencies, particularly vitamin E. These can include poor muscle coordination (ataxia), balance problems, muscle weakness, and difficulties with speech. Vision problems, such as night blindness and progressive loss of central vision, can also develop, often becoming more pronounced with age. Some individuals may also experience curvature of the spine (scoliosis) and, rarely, heart muscle problems (cardiomyopathy).
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Affected organs
The primary organs affected in abetalipoproteinaemia are the small intestine, liver, and the nervous system. The small intestine is unable to properly absorb fats, leading to their accumulation within its cells and malabsorption into the bloodstream. The liver is also impacted as it cannot produce the very low-density lipoproteins (VLDL) essential for transporting fats.
Crucially, the nervous system is significantly affected due to chronic deficiencies of fat-soluble vitamins, especially vitamin E. This deficiency can cause damage to nerve cells, leading to a range of neurological issues. The eyes are also vulnerable to damage from vitamin A deficiency, leading to vision deterioration.
Risks & severity
Abetalipoproteinaemia is a serious condition with lifelong implications if not managed proactively. The severity of symptoms can vary, but generally, early diagnosis and treatment are crucial to minimise long-term complications, particularly neurological damage. Untreated individuals face progressive neurological decline, severe vision loss, and potentially life-threatening cardiac complications.
While the condition is present from birth, the neurological and visual problems tend to worsen over decades. Lifelong dietary management and high-dose vitamin supplementation are essential to mitigate the risks associated with the condition. The exact prevalence of abetalipoproteinaemia is not well established, but it is considered a very rare disorder worldwide.
Genetic causes
Abetalipoproteinaemia is caused by pathogenic variants in the MTTP gene. The MTTP gene provides instructions for making a protein called microsomal triglyceride transfer protein. This protein plays a critical role in the assembly and release of lipoproteins, specifically chylomicrons and very low-density lipoproteins (VLDL), which are responsible for transporting fats from the intestine and liver, respectively, into the bloodstream [PMID:33671077].
When there are pathogenic variants in the MTTP gene, the microsomal triglyceride transfer protein either isn't produced or doesn't function correctly. This prevents the normal assembly and release of chylomicrons and VLDL, leading to the accumulation of fats within intestinal and liver cells and a severe lack of these crucial fats in the blood. This disruption to fat transport directly impairs the absorption and distribution of essential fat-soluble vitamins, leading to the clinical features observed in abetalipoproteinaemia [PMID:11340156].
- MTTP microsomal triglyceride transfer proteinThe MTTP gene provides instructions for the microsomal triglyceride transfer protein, which is essential for producing lipoproteins that transport fats and fat-soluble vitamins throughout the body.
Inheritance pattern
Abetalipoproteinaemia has an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of a pathogenic variant in the MTTP gene - one from each parent - to develop the condition.
Parents who each carry one copy of the pathogenic variant (meaning they are 'carriers') do not usually display symptoms themselves, as they have one functional copy of the gene. However, for each child born to two carrier parents, there is a 25% chance of the child inheriting two pathogenic variants and developing abetalipoproteinaemia, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting no pathogenic variants and not being a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing abetalipoproteinaemia typically involves a combination of clinical evaluation, blood tests, and genetic testing. Initial suspicions may arise from symptoms such as chronic diarrhoea, failure to thrive in infancy, or early-onset neurological issues. Blood tests often reveal very low levels of cholesterol, triglycerides, and fat-soluble vitamins (especially vitamin E) and an absence of apolipoprotein B, a key component of the affected lipoproteins.
Confirmation of the diagnosis is usually achieved through genetic testing, which identifies pathogenic variants in the MTTP gene. Referral to a clinical genetics service via NHS pathways, typically by a paediatrician or gastroenterologist, is the standard route for diagnosis and genetic counselling. The relevant NHS National Genomic Test Directory R-code for inherited metabolic disorders (e.g., R104) would apply for this type of testing.
Management & lifestyle
Managing abetalipoproteinaemia primarily focuses on dietary interventions and high-dose supplementation of fat-soluble vitamins (A, D, E, K) to manage symptoms and prevent progressive neurological and visual damage [PMID:11340156]. A diet that restricts long-chain fats but includes medium-chain triglycerides (MCTs) may be recommended, as MCTs are absorbed differently and do not require the affected lipoprotein pathway.
Regular monitoring by a multidisciplinary team, including a gastroenterologist, neurologist, ophthalmologist, dietitian, and genetic counsellor, is essential. Surveillance typically involves periodic blood tests to check vitamin levels, neurological assessments, and eye examinations. Genetic counsellors can provide information about the inheritance pattern and implications for family planning for affected individuals and their relatives within the NHS Genomic Medicine Service.
It is important that individuals with abetalipoproteinaemia do not make significant dietary or supplement changes without guidance from their healthcare team.
UK care pathway
In the UK, individuals suspected of having abetalipoproteinaemia would typically enter the NHS Genomic Medicine Service pathway. Referral, often from a GP, paediatrician, or specialist, would lead to a clinical genetics clinician. These specialists can assess the individual, arrange for genetic testing under the NHS National Genomic Test Directory (GMS R-code as appropriate), and coordinate with suitable specialists.
Access to genetic counsellors is also an integral part of this pathway, providing essential support and information to patients and families regarding genetic inheritance, implications, and support networks.
Frequently asked questions
What happens if abetalipoproteinaemia is not treated?
Without treatment, the progressive deficiency of fat-soluble vitamins, particularly vitamin E, can lead to severe and irreversible neurological damage, including problems with balance and coordination, muscle weakness, and loss of sensation. Vision can also significantly deteriorate, potentially causing blindness, and heart problems may develop.
Are diet changes necessary for abetalipoproteinaemia?
Yes, dietary changes are a cornerstone of managing abetalipoproteinaemia. Typically, a diet low in long-chain fats is advised, with a focus on types of fats that are easier to absorb, like medium-chain triglycerides (MCTs). However, any dietary changes should only be made under the guidance of a specialist dietitian.
Do people with abetalipoproteinaemia need lifelong vitamin supplements?
People with abetalipoproteinaemia generally require lifelong, high-dose supplementation with fat-soluble vitamins (A, D, E, and K). This is crucial to prevent the severe deficiencies and subsequent health complications associated with the condition. The specific doses and types of supplements are determined by a healthcare team.
Can abetalipoproteinaemia be cured?
Currently, there is no cure for abetalipoproteinaemia. However, the condition is manageable through lifelong adherence to dietary modifications and high-dose vitamin supplementation. Early and consistent treatment can significantly improve the quality of life and prevent many of the severe long-term complications.
How does abetalipoproteinaemia affect family planning?
Because abetalipoproteinaemia is an autosomal recessive condition, individuals with a family history may wish to speak to a genetic counsellor. They can explain the inheritance pattern, discuss the chances of other family members being carriers, and outline options for family planning, including genetic testing for partners and prenatal diagnosis, if desired.
References
- FORSYTH CC, LLOYD JK, FOSBROOKE AS. A-BETA-LIPOPROTEINAEMIA. Archives of disease in childhood. 1965. PMID: 14259271
- Wolff OH. A-beta-lipoproteinaemia. Ergebnisse der inneren Medizin und Kinderheilkunde. 1965. PMID: 5320209
- Stevenson VL, Hardie RJ. Acanthocytosis and neurological disorders. Journal of neurology. 2001. PMID: 11284140
- Gracey M, Burke V, Anderson CM. Medium chain triglycerides in paediatric practice. Archives of disease in childhood. 1970. PMID: 4918706
- Wolff O. A-beta-lipoproteinaemia. Developmental medicine and child neurology. 1965. PMID: 5862046
- Arias M. Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia. Neurologia. 2019. PMID: 27460185
- Fosbrooke A, Choksey S, Wharton B. Familial hypo-beta-lipoproteinaemia. Archives of disease in childhood. 1973. PMID: 4733643
- Hardie RJ. Acanthocytosis and neurological impairment--a review. The Quarterly journal of medicine. 1989. PMID: 2687930