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Familial hypobetalipoproteinaemia
This condition typically results from genetic changes affecting lipid metabolism, particularly the APOB gene. While often benign, some individuals may experience digestive issues or liver involvement. It affects approximately 1 in 3,000 people in its most common form.
Overview
Familial hypobetalipoproteinaemia (FHBL) is a genetic condition where the body produces unusually low levels of 'bad' cholesterol (low-density lipoprotein cholesterol, or LDL-C) and other fat-carrying particles called lipoproteins. These lipoproteins are essential for transporting fats and cholesterol around the body. In FHBL, the reduced production or increased breakdown of these particles leads to their low concentration in the blood [PMID:24607772].
FHBL is typically inherited and can range from being asymptomatic - meaning individuals have no noticeable health problems - to causing more significant symptoms, particularly related to the digestive system or liver. The condition is considered rare, with heterozygous forms affecting approximately 1 in 3,000 individuals [PMID:24607772]. Its discovery often occurs during routine blood tests that show unexpectedly low cholesterol levels.
Symptoms & clinical features
Many individuals with familial hypobetalipoproteinaemia, especially those with one altered copy of the causative gene (heterozygous), experience no symptoms at all. Their extremely low cholesterol levels are often discovered incidentally during routine health checks [PMID:33604077].
However, some people, particularly those with more severely affected lipid metabolism, may develop symptoms. These can include digestive issues such as steatorrhoea (fatty, pale stools), abdominal discomfort, or malabsorption of fat-soluble vitamins (A, D, E, K). In some cases, liver involvement, such as fatty liver (hepatic steatosis), may occur. Neurological symptoms have been reported in very rare, severe forms, but these are not typical for most individuals with FHBL.
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Affected organs
The primary organs affected in familial hypobetalipoproteinaemia are the liver and the digestive system, particularly the small intestine. The liver is central to producing lipoproteins, which are particles that carry fats and cholesterol in the blood. When the production or function of these particles is impaired, fats can build up in liver cells, potentially leading to a fatty liver.
The small intestine also plays a crucial role in absorbing dietary fats and forming certain lipoproteins. Impairment here can lead to difficulties absorbing fats and fat-soluble vitamins from food. In rare, severe cases, the nervous system might be affected due to prolonged malabsorption of vitamin E, which is vital for nerve health. However, this is uncommon in the typically observed forms of FHBL.
Risks & severity
The severity of familial hypobetalipoproteinaemia can vary significantly, even within the same family. Most individuals who inherit one copy of a genetic alteration associated with FHBL (heterozygous state) remain healthy and symptom-free throughout their lives. Their exceptionally low levels of LDL-cholesterol are often considered beneficial, potentially offering protection against common cardiovascular diseases.
However, in a small proportion of individuals, particularly those who inherit two altered copies of the gene (homozygous or compound heterozygous state), or those with specific types of gene changes, the condition can be more severe. This may involve chronic digestive problems, significant malabsorption of fat and fat-soluble vitamins, and progressive liver dysfunction. Neurological complications due to severe vitamin E deficiency are rare but possible in the most severe forms. Lifelong monitoring and management are crucial for those with symptomatic FHBL.
Genetic causes
Familial hypobetalipoproteinaemia is most commonly caused by changes in the APOB gene. The APOB gene provides instructions for making apolipoprotein B, a critical protein found on the surface of various lipoproteins, including chylomicrons, VLDL (very low-density lipoprotein), and LDL (low-density lipoprotein). These lipoproteins are responsible for transporting fats and cholesterol from the intestine and liver to other parts of the body [PMID:24607772].
Pathogenic variants in APOB typically lead to either a reduced production of apolipoprotein B or the production of a shortened, non-functional version of the protein. This impairment in apolipoprotein B affects the assembly and secretion of lipoproteins from the liver and intestine, resulting in fewer lipoproteins, and consequently, lower levels of cholesterol and triglycerides in the blood. Other genes involved in lipid metabolism can also cause similar conditions, but APOB is the most frequently implicated gene in FHBL [PMID:33604077].
- APOB apolipoprotein BThe APOB gene provides instructions for making apolipoprotein B, a key protein involved in the transport of fats and cholesterol throughout the body, playing a central role in lipid metabolism.
Inheritance pattern
Familial hypobetalipoproteinaemia generally follows an autosomal dominant inheritance pattern. This means that a person only needs to inherit one copy of an altered gene from one parent to be affected by the condition. If one parent has FHBL, there is a 50% chance with each pregnancy that their child will also inherit the altered gene and develop the condition, regardless of the child's sex.
even though the condition is inherited in an autosomal dominant manner, the presentation can vary widely. Some family members with the altered gene may have no symptoms, while others may experience mild or, rarely, more severe issues. Genetic counselling can help families understand the inheritance risks and implications for their relatives.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of familial hypobetalipoproteinaemia is typically suspected when routine blood tests show persistently low levels of total cholesterol, LDL-cholesterol, and apolipoprotein B. After initial blood tests, a definitive diagnosis is confirmed through genetic testing to identify pathogenic variants in causative genes like APOB [PMID:33604077].
In the UK, genetic testing for FHBL can be accessed through the NHS Genomic Medicine Service (GMS). A GP or specialist, such as a lipid specialist or gastroenterologist, might refer an individual to a clinical genetics service for assessment and genetic counselling. The relevant R-code for genomic testing may be used to guide testing panels. Clinical geneticists and genetic counsellors can help interpret results and discuss the implications for the patient and their family.
Management & lifestyle
The management of familial hypobetalipoproteinaemia is typically tailored to the individual's symptoms and the severity of their condition. For most individuals with FHBL who are asymptomatic, no specific treatment is usually required, and their low cholesterol levels may be considered protective against cardiovascular disease. Regular monitoring of lipid levels and general health may be advised.
For those who experience symptoms, such as digestive issues or signs of vitamin deficiency, management focuses on supportive care. This may include dietary adjustments to manage steatorrhoea and supplementation with fat-soluble vitamins (A, D, E, K) to prevent deficiencies. Monitoring for liver involvement, such as fatty liver, might also be part of the care plan. All management decisions should be made in consultation with healthcare professionals, often within the NHS specialist clinics, such as metabolic or gastroenterology services.
UK care pathway
In the UK, individuals suspected of having familial hypobetalipoproteinaemia typically enter the NHS care pathway via a referral from their GP or a specialist to a clinical genetics service. These services are part of the NHS Genomic Medicine Service (GMS).
Genetic counsellors within these services provide essential support, offering information about the condition, inheritance patterns, and the implications of genetic testing for individuals and their families. They can also help coordinate genetic testing, which is guided by specific R-codes for lipid disorders. Management for confirmed cases often involves a multidisciplinary team, potentially including lipid specialists, gastroenterologists, and dietitians, depending on the individual's symptoms.
Frequently asked questions
What does it mean to have low 'bad' cholesterol?
Having low 'bad' cholesterol, specifically LDL-C, is generally considered beneficial for heart health. In familial hypobetalipoproteinaemia, these levels are naturally very low due to genetic factors, and this often reduces the risk of common cardiovascular diseases.
Will my children inherit familial hypobetalipoproteinaemia?
Familial hypobetalipoproteinaemia is typically inherited in an autosomal dominant pattern. If you have the condition, each of your children has a 50% chance of inheriting the altered gene. A genetic counsellor can provide more personalised information about inheritance risks.
Do I need to change my diet if I have this condition?
For many people with familial hypobetalipoproteinaemia, no specific dietary changes are needed if they are asymptomatic. However, if you experience digestive symptoms or vitamin deficiencies, a healthcare professional, such as a dietitian, may suggest dietary adjustments or vitamin supplements.
Can familial hypobetalipoproteinaemia cause liver problems?
In some individuals with familial hypobetalipoproteinaemia, especially those with more severe forms, fat can accumulate in the liver, leading to a fatty liver (hepatic steatosis). Regular monitoring by a doctor can help detect and manage any liver involvement.
How is familial hypobetalipoproteinaemia diagnosed in the UK?
Diagnosis in the UK usually starts with routine blood tests showing persistently low cholesterol. A referral to a clinical genetics service via your GP or specialist for genetic testing, guided by the NHS Genomic Medicine Service, can then confirm the diagnosis.
References
- Lodi R, Rinaldi R, Gaddi A. Brain and skeletal muscle bioenergetic failure in familial hypobetalipoproteinaemia. Journal of neurology, neurosurgery, and psychiatry. 1997. PMID: 9219741
- Vongsuvanh R, Hooper AJ, Coakley JC. Novel mutations in abetalipoproteinaemia and homozygous familial hypobetalipoproteinaemia. Journal of inherited metabolic disease. 2007. PMID: 18027103
- Roma E, Klontza D, Kairis M. Familial hypobetalipoproteinaemia. Helvetica paediatrica acta. 1984. PMID: 6543837
- Di Leo E, Magnolo L, Bertolotti M. Variable phenotypic expression of homozygous familial hypobetalipoproteinaemia due to novel APOB gene mutations. Clinical genetics. 2008. PMID: 18492086
- Araki W, Hirose S, Mimori Y. Familial hypobetalipoproteinaemia complicated by cerebellar ataxia and steatocystoma multiplex. Journal of internal medicine. 1991. PMID: 1997645
- Fouchier SW, Sankatsing RR, Peter J. High frequency of APOB gene mutations causing familial hypobetalipoproteinaemia in patients of Dutch and Spanish descent. Journal of medical genetics. 2005. PMID: 15805152
- Non-alcoholic Fatty Liver Disease Study Group, Lonardo A, Bellentani S. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2015. PMID: 26454786
- Farese RV Jr, Linton MF, Young SG. Apolipoprotein B gene mutations affecting cholesterol levels. Journal of internal medicine. 1992. PMID: 1619387