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Rarer genetic conditions

Hypobetalipoproteinaemia and abetaliproteinaemia

Familial hypobetalipoproteinaemia

otherwise known as FHBL and hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a condition characterized by lifelong low levels of cholesterol and triglyceride fats in the blood (low concentrations of chylomicrons, VLDL and LDL) and is thought to affect between 1 in 1,000 to 3,000 of the population. The severity of signs and symptoms experienced by people with the condition varies significantly. This can range from those mildly affected with few problems absorbing fats from the diet and no other related signs and symptoms. Others can develop an abnormal build up of fats in the liver causing a fatty liver (hepatic steatosis) or non-alcoholic fatty liver disease (NAFLD) and those more severely affected can progress to non-alcoholic steatohepatitis 9NASH) and chronic liver disease (cirrhosis). Individuals with severe FHBL have greater difficulty absorbing fats as well as fat-soluble vitamins such as vitamin E and vitamin A which can lead to excess fat loss in the faeces (steatorrhea). In childhood, these digestive problems can result in an inability to grow or gain weight known as failure to thrive.

Most cases are caused by mutations in the ApoB gene which provides instructions for ApoB proteins, which are components of all the lipoproteins which transport fats and cholesterol in the blood (apart from HDL). Normally 2 versions of ApoB are made, a short version (apoB48) being made by the gut, a full length version (apo B100) being made by the liver. Those with FHBL also make an abnormally short version in the liver. The most severely shortened versions cannot bind with lipoproteins and transport fats and cholesterol effectively. Those who have only slightly shortened versions do have some function, so the condition will be more serious if both copies of the ApoB gene are severely shortened. As well as mutations in the the ApoB gene, other mutations have been found which account for a small number of causes . The condition is inherited as an autosomal co-dominant pattern which means copies of the gene from both parents are active and both copies influence the genetic trait – in FHBL a change in one copy of the apoB gene can cause the condition but changes in both copies causes more severe liver problems.


Abetalipoproteinaemia is also known as Bassen Kornzweig syndrome; Microsomal triglyceride transfer protein deficiency disease; Microsomal triglyceride transfer protein deficiency.

Abetalipoproteinaemia is a very rare conditions with 100 cases described worldwide. The condition is characterized by the inability to absorb dietary fats, cholesterol and fat soluble vitamins. It is caused by mutations in the MTTP gene which provides instructions for making a protein known as the microsomal triglyceride transfer protein (MTP). This protein is essential in producing the beta-lipoproteins in the liver and intestine which transport fats, cholesterol and fat soluble vitamins from intestine to blood where the nutrients are taken up by the body tissues. These nutrients are essential for growth, development and maintenance of body cells and tissues. The presence of this gene mutation leads to MTP proteins with reduced or absent function which are then unable to transfer fats onto the beta lipoproteins. This in turn then leads to severe reduction in the body’s ability to absorb dietary fats and fat soluble vitamins from the digestive tract to blood stream causing health and nutritional deficiencies such as nutritional and neurological problems.

Signs and symptoms of Abetalipoproteinaemia appear in the first few months of life, include failure to thrive, stool abnormalities (diarrhoea and steatorrhea), with other features developing later including slower intellectual development, poor muscle co-ordination and a degenerative eye condition, retinitis pigmentosa. These are mainly the result of poor absorption and transport of essential fatty acids and vitamin E. Therefore early diagnosis and treatment with high dose vitamin E therapy and fatty acid supplements may help improve these nervous system abnormalities. Early diagnosis of the condition will mean a better long term outlook but undiagnosed and untreated can lead to severe, often fatal disease.

Abetalipoproteinaemia is inherited in an autosomal recessive manner meaning the person must have a mutation in both copies of the gene in each cell, inherited from each parent (the carrier) – when 2 carriers have children, each child has 25% (1 in 4) chance to be affected, 50% (1 in 2) chance to be unaffected carrier, 25% chance to be unaffected and not be a carrier of Abetalipoproteinaemia.

Ref: https://ghr.nlm.nih.gov/condition/abetalipoproteinemia

Severe polygenic hypercholesterolaemia

Common 1:20 – 1:100

Polygenic hypercholesterolaemia describes the small effect of many genes increasing our cholesterol levels and not just one single dominant gene as in a monogenic condition such as Familial Hypercholesterolaemia. Although at least 140 genes are known to have an effect on LDL-cholesterol levels, 12 common “LDL raising” gene variants (or SNPs) with the largest effects on LDL-cholesterol have been identified in genetic testing laboratories. Each of these common gene variants increases cholesterol level by only a small amount (less than 10%) on its own, however if a person has inherited several of these gene variants, not just one or two, then these can cause a severe increase in their cholesterol level in a cumulative manner.

Doctors who test people who they think have FH believe that this is the most frequent cause of high cholesterol in people where no dominant FH causing gene is found in routine genetic tests. Now lipid clinics can offer what is known as next generation sequencing where they can look for the major dominant gene causes as well as these 12 common LDL raising variants at the same time to see which is the cause for the high cholesterol. Although high cholesterol caused by this “polygenic” condition may not be present from birth and may not therefore be as “severe” as monogenic FH, people are still at risk of developing cardiovascular disease and should still be offered cholesterol lowering medication to reduce their levels and also address any other risk factors they may have. As all of the gene variants in polygenic hypercholesterolaemia are not inherited together, cascade testing i.e. the genetic testing of other family members of people, is not recommended as it is unlikely to be cost effective. Instead, relative can be offered cholesterol testing and if found to have a high cholesterol then they should receive appropriate advice regarding cholesterol and other risk factors.

People who have had a single FH causing gene mutation identified (monogenic FH) can also have an additional background of “polygenic” LDL-cholesterol raising variants. For example, of two sisters who were tested for FH, the first sister had a total cholesterol level of 15 mmol/L and the second sister had a total cholesterol level of 8.5mmol/L. The first sister was found to have a known FH causing single gene plus a polygenic background, whereas the second sister did not have the genetic alteration but did show the polygenic background. Both sisters met the diagnostic criteria for FH, but only the first sister required further cascade testing of her family.

Further investigation

For those who are found to have a low polygenic or “SNP score”, this can indicate the presence of an undiagnosed single FH causing gene. Specialists recognise there are at least 10% of those diagnosed clinically as definite FH (e.g. having tendon xanthoma) in which no monogenic mutation can be found and those with an additional low SNP score may eligible for the whole genome sequencing to find a novel cause (indeed some have been recruited for the 100.000 Genome Project).

Autosomal recessive hypercholesterolaemia (ARH- LDLRAP)

Autosomal recessive hypercholesterolaemia (ARH) is a rare condition which has a similar clinical features to the rarer form of familial hypercholesterolamia (FH) known as homozygous FH (HoFH). Comparative studies have shown that it is a less severe condition which responds better to cholesterol lowering medication than HoFH. It is thought to be milder than the receptor negative form of HoFH and more so resembles that of the receptor defective HoFH. There are thought to be only 50 known affected individuals, with rare cases occurring worldwide.

The condition is caused by a mutation in the ARH gene, which results in the complete loss of function of the ARH protein which is needed for the LDL receptor to take up LDL from the blood and into the cell (internalization of the LDLR complex). A recent 2018 study found that despite intensive treatment, LDL cholesterol levels in people with ARH remained far from treatment targets.


Lipodystrophy is a medical term used to describe a group of rare conditions where the body is unable to produce and maintain healthy fat tissue. It is characterized by a variable loss of body fat (adipose) tissue which is in turn classified based on the distribution of fat loss sustained. This loss of fat can affect the whole body (generalized), only certain body regions (partial) or small areas under the skin (localized). The condition can be caused by either a genetic defect or mutation or is known as an acquired lipodystrophy.

The two main genetic lipodystrophies are known as congenital generalized lipodystrophy (autosomal recessive), and familial partial lipodystrophy (autosomal dominant). Several genes have been identified which include AGPAT2 gene, BSCL2 gene in congenital generalized lipodystrophy (CGL), and LMNA gene and PPARG gene in Familial Partial Lipodystrophy.

There are 3 main acquired lipodystrophies. These are known as acquired generalized lipodystrophy which is a gradual loss of subcutaneous fat beginning in childhood/adolescence; acquired partial lipodystrophy characterized by gradual loss of fat from the upper body and frequently associated with autoimmune diseases, and HIV associated lipodystrophy in HIV infected patients following use of anti -retroviral therapy.

Metabolic abnormalities associated with loss of fat storage capacity in this condition include insulin resistance which can lead to development of type 2 diabetes, high plasma triglyceride levels and hepatic steatosis which can progress to liver cirrhosis. The severity is usually related to the extent of the adipose tissue loss.

Management of lipodystrophy focuses on preventing and treating the above complications, with diet and exercise playing an important role, and the use of medicines to treat diabetes and dyslipidaemias such as high triglycerides.

Information and support


Lysosomal acid lipase deficiency (LALD)

Lysosomal acid lipase deficiency (also known as cholesterol ester storage disorder (CESD), Wolman’s disease or LAL deficiency) is a rare condition affecting only a few people in the UK.

It belongs to a group of medical conditions, described as “lysosomal storage disorders”.

LAL is an enzyme that is responsible for breaking down fats in a part of the cell called the lysosome. Because the LAL enzyme is missing, or deficient, fats build up in the body's cells.  This appears to happen mostly in the liver, gastrointestinal and cardiovascular systems.  People inherit the disorder by receiving an altered gene from both their mother and father. People with one altered gene are carriers of the gene but do not have symptoms.

All ages can be affected, from infants through to adults. People who present with LAL deficiency often have high cholesterol and triglycerides, and a very low HDL-cholesterol level. LAL deficiency is under diagnosed, largely because the symptoms mimic other more common conditions.

It is estimated that between 1 in 500,000 and 1 in 1,000,000 babies present with LALD and that a further 1 in 40,000 to 1 in 300,000 people present later in life, either in childhood or adulthood.  Those diagnosed in infancy often have a more aggressive form of LALD than those diagnosed later in life.  

Not everyone is equally affected by the condition and symptoms can vary from person to person.  However this is a serious life threatening condition.  Symptoms range from difficulty digesting and absorbing food, growth failure, weight loss, fatty stools and liver failure to abdominal pain, fatigue, diarrhoea, nausea, loss of appetite, itchy skin and a swollen abdomen.

Tangier disease

Tangier disease is a rare inherited condition characterized by either the complete absence or extremely low levels of high-density lipoproteins (HDL or good cholesterol) in the blood. LDL cholesterol levels (bad cholesterol) can also be reduced, while triglyceride levels can be high. The pattern of inheritance is autosomal recessive (see glossary below).

The cause of Tangier disease has been identified as a loss of function mutation in the ABCA1 (ATP-binding cassette transporter A1) gene which codes for a cell surface protein that is important in the process of reverse cholesterol transport. ABCA1 allows the movement of cholesterol from inside the cell to apolipoprotein AI (apoA-I), the major protein which makes up HDL. When two ABCA1 gene mutations are present, the cell is no longer able to transfer cholesterol out of the cell to HDL particles.

Physical signs of Tangier disease are mainly due to cholesterol deposits accumulating in characteristic places in the body. These include enlarged, yellow or orange coloured tonsils (due to cholesterol deposits) and they can also occur in other areas such liver, spleen and lymph nodes, and also nerves which can cause peripheral neuropathy leading to a loss of sensation. Very rarely the condition can cause clouding of the cornea in the eye (known as corneal opacity) and reduced vision. The condition can be associated with increased risk of cardiovascular disease.

Further information


Hepatic lipase deficiency

Also known as: LIPC deficiency, HL deficiency, hyperlipidemia due to hepatic triglyceride lipase deficiency

Hepatic lipase deficiency is a very rare condition where only a few affected families have been reported in the scientific literature. It can be characterized by increased levels of triglycerides and cholesterol, in the blood, in particularly high levels of HDL cholesterol and low LDL levels.

Hepatic lipase deficiency is inherited in an autosomal recessive manner and is caused by changes (mutations) in the LIPC gene. The LIPC gene is responsible for making an enzyme known as hepatic lipase which is produced by liver cells and is released to convert the triglyceride (fat) rich VLDL and IDL to LDL particles. The enzyme also has an important role in the transport of HDL to the liver, where its cholesterol and triglyceride content can be recycled or removed from the body. Therefore a mutation or alteration in this gene will interfere with the action of the enzyme and as a result the VLDL and IDL particles will not be effectively converted to LDL, thus resulting in increase VLDL and IDL lipoproteins a low LDL level.

Hepatic lipase deficiency is thought to be associated with an increased risk of developing premature coronary artery disease (30-70% of people) – presenting symptoms vary between people and therefore treatment is tailored for each individual. Additional research is needed on the long-term outlook of people with this condition.

For further information


Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (means cerebro (brain) and tendinous (tendons)) is a condition caused by the abnormal storage of fats (lipids) in diverse areas of the body including the brain and in tendons attaching muscle to bone (commonly in the hands, elbows, knees, neck and Achilles tendon in the heel). In this condition certain fats related to cholesterol cannot be broken down properly so they accumulate as fatty deposits or nodules known as xanthomas. This is due to a mutation in the CYP27A1 gene which provides instructions for a key enzyme required for normal cholesterol metabolism. It occurs in only 1 per million of people worldwide (but is much more common in Morrocan Jewish population where it is 1 in 108 people).

Those affected with the condition can develop neurological problems in early adulthood due to xanthomas deposited in the brain, which accumulate in the myelin sheath which protects nerves and causes damage and disruption to the nerve signals in the brain. This may cause seizures (epilepsy) speech impairment, peripheral neuropathy – loss of sensation in arms and legs, hallucinations, depression. The tendon xanthomas can cause discomfort and interfere with tendon flexibility but sometimes are not easy to detect under the skin. Other features include cataracts in the eyes (clouding of the lens) and chronic diarrhoea in childhood. Those affected with the condition are at increased risk of CVD or respiratory problems due to accumulation of fats in the heart and lungs.

An autosomal recessive genetic condition means two copies of an abnormal gene must be present in order for the disease or trait to develop i.e. in both parents. The risk for 2 carrier parents to pass the gene is 25% and the risk to have a child who is a carrier is 50% and 25% for the child to receive 2 normal genes.

Further information on diagnosis and treatment