Rarer genetic conditions

Familial hypobetalipoproteinaemia (FHBL)

Familial hypobetalipoproteinaemia (FHBL) is a genetic condition which causes low levels of blood cholesterol and triglycerides throughout your life. It can sometimes lead to health problems due to not being able to absorb fats and vitamins.

It is also known as FHBL and hypobetalipoproteinemia.

With FHBL, your body is less able to absorb fats from the food you eat and transport them around your body. Fats have essential roles in your body and are needed for absorbing some vitamins from food. A lack of fats and vitamins can lead to long term health problems.

Sometimes the condition is very mild and doesn’t cause any symptoms at all, but for others it can be more serious. It varies from person to person.

Between 1 in 1,000 and 1 in 3,000 people are thought to have FHBL.

What causes FHBL?

FHBL is passed down in the genes. It is usually caused by faults in the ApoB gene which codes for proteins called the ApoB proteins. These form part of your lipoproteins which are needed to transport fats around your body.

We have two versions of the ApoB protein – a long one called ApoB100 and a short one called ApoB48. With FHBL, the long one, ApoB48, is too short:

If your ApoB protein is only slightly shortened, your lipoproteins can still do their job and transport some fats, so the condition will be milder.
If your ApoB is very short, it can’t bind to the lipoproteins so the lipoproteins can’t transport fats. This means the fat you eat doesn’t enter your blood stream and your blood fats will be low.

Faults in a small number of other genes are also known to cause FHBL and there could be others that haven’t been identified yet.

How is FHBL passed down through families?

FHBL is autosomally co-dominant. This means:

if you inherit a faulty copy of a gene from one parent you will have the disease but it is likely to be mild and probably won’t cause symptoms
if you inherit a faulty copy of a gene from both parents, the disease will be more serious. This is much rarer.

How mild or severe your FHBL is depends on which genes are involved and whether you inherit a faulty copy of a gene from one or both parents.

What are the symptoms of FHBL?

Mild cases can cause minor problems absorbing fats but no signs or symptoms. More severe cases can cause serious problems related to not being able to absorb fats and vitamins.

Vitamin deficiency. A lack of fat-soluble vitamins such as vitamin E and vitamin A can lead to nerve and eye damage.
Liver disease. Not being able to transport fats around the body properly can cause fat to build up in the liver, leading to liver disease. This includes fatty liver (hepatic steatosis) or non-alcoholic fatty liver disease (NAFLD). In more severe cases, this may progress to non-alcoholic steatohepatitis (NASH) and chronic liver disease (cirrhosis).
Digestive problems. In more severe cases, the fat you eat may simply pass through your gut. This will cause excess fat in the feaces (poo). This is called steatorrhea and can be seen as pale coloured poo that floats and is difficult to flush. FHBL can also cause diarrhoea.
Growth problems in children. In childhood, not being able to absorb fats and vitamins can affect the child’s growth and development.

How is FHBL diagnosed and treated?

Genetic testing can be used to diagnose FHBL. Other tests include:

blood tests to look at your blood fats. FHBL causes low levels of the lipoproteins chylomicrons, VLDL cholesterol and LDL cholesterol. LDL cholesterol levels are usually between 0.5 – 1.3mmol/L in FHBL, whereas the target for healthy adults is below 3mmol/L

a physical exam
questions about family history
questions about any symptoms you may have.

You will be treated by a specialist in blood fats. Management can include vitamin supplements and eating less fat.

Find out more

MedlinePlus

NIH Genetic and Rare Disease Information Center

Abetalipoproteinaemia

Abetalipoproteinaemia is a genetic condition which causes low or absent levels of cholesterol and triglycerides in your blood. This happens because your body can’t absorb fats and fat-soluble vitamins from the food you eat, which can lead to serious health problems.

It’s similar to FHBL but tends to be more serious.

Abetalipoproteinaemia is also known as Bassen Kornzweig syndrome, Microsomal triglyceride transfer protein (MTP) deficiency disease, and Microsomal triglyceride transfer protein deficiency.

It’s very rare, there are only 100 known cases worldwide.

What causes abetalipoproteinaemia?

Abetalipoproteinaemia is passed down in the genes. It’s caused by faults (or mutations) in a gene called the MTTP gene, which codes for a protein known as the microsomal triglyceride transfer protein (MTP).

This protein is involved in transporting fats and vitamins from the intestines into the blood and around the body.

With abetalipoproteinaemia, your MTP protein doesn’t work, or doesn’t work as well as it should. This means the your body can’t absorb enough fats and vitamins from your gut and carry them around your body.

How is abetalipoproteinaemia passed through families?

The condition is autosomally recessive which means you need to inherit a faulty copy of the gene from both parents to have it – so both parents must either have the condition themselves or be carriers.

What are the symptoms of abetalipoproteinaemia?

Fats and vitamins are essential for growth and development during childhood and for our cells and tissues to stay healthy throughout life. The symptoms of abetalipoproteinaemia are caused by fats and vitamins not being absorbed from food, especially vitamin E, as well as vitamins A, D and K.

Some symptoms appear in the first few months of life:

diarrhoea, caused by too much fat in the stools (poo)
fatty stools (known as steatorrhea) which are pale and difficult to flush
growing and developing slowly (known as 'failure to thrive').

Other effects develop later on and involve the nervous system and eyes:

slower intellectual development
poor muscle co-ordination, movement and balance (ataxia)
eye problems including retinitis pigmentosa, a condition which gets worse with time
anaemia, where you don’t have enough red blood cells, which can make you very tired
other blood problems such as misshapen red blood cells and problems with clotting, which means you bruise and bleed easily
a build-up of fat in the liver, leading to fatty liver disease which can become more serious with time.

How is abetalipoproteinaemia diagnosed?

Getting diagnosed early means treatment can be started early and can improve symptoms and long term health. Without diagnosis and treatment, the disease can be very serious and can even be fatal.

A diagnosis can be confirmed with a genetic test. Once you or your child have been diagnosed, you or you child will be treated by an expert in blood fats.

How is abetalipoproteinaemia treated?

Treatments include:

supplements with high doses of Vitamin E, other vitamins and fatty acids (fats)
changes to the diet such as cutting down on fat.

Find out more

BMJ Best Practice

NIH GeneReviews

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 or ARH- LDLRAP)

Autosomal recessive hypercholesterolaemia (ARH) is an “ultra” rare genetic condition which causes very high LDL cholesterol levels which puts you at risk of heart disease at an early age. Only around 50 people are known to have it worldwide (1 in a million people).

ARH is similar to the rarer form of familial hypercholesterolamia (FH) known as homozygous FH (HoFH), but ARH is less severe and responds better to cholesterol-lowering medication.

What causes ARH?

The condition is caused by a fault (mutation) in the ARH gene. This gene codes for the ARH protein which is needed for LDL-receptors to remove LDL cholesterol (bad cholesterol) from the blood. Without it, blood cholesterol rises too high.

LDL receptors are small structures that carry cholesterol from the blood into your cells. LDL-receptors are also involved in a condition called HoFH which can be:

receptor negative which is more serious
receptor defective which is milder

ARH is thought to be milder than the receptor negative form of HoFH, and resembles receptor defective HoFH. This means you will have some working LDL-receptors, so can remove some cholesterol from your blood.

How is ARH passed through families?

How is ARH diagnosed?

The condition is diagnosed through a combination of:

genetic testing to identify mutations in the ARH gene (LDLRAP1)
lipid profile (looking at your blood fat levels using a blood test). LDL cholesterol is severely raised cholesterol, typically higher than 10mmol/L compared to the usual target of below 3mmol/L.
clinical assessment including imaging and family history.

ARH can also have signs such as:

fatty lumps under the skin (cutaneous xanthomas)
premature atherosclerotic coronary vascular disease (ASCVD) - where the blood vessels supplying the heart become clogged up at an early age
atheromatous involvement of the aortic valve (thickening of the valve that allows blood to flow away from the heart due to a build up of fat).

As it is autosomally recessive, both parents have normal LDL cholesterol levels.

Lipodystrophy

Lipodystrophy is the name for a group of rare conditions where the body can’t make and maintain healthy fat tissue (adipose tissue), causing a loss of body fat.

The amount of fat lost and where in the body it's lost from varies. Lipodystrophies are categorised according to where in the body fat is lost from:

the whole body (generalized)
only certain areas of the body (partial)
small areas under the skin (localized).

Causes and types of lipodystrophy

Lipodystrophy can be caused by a genetic defect (mutation) meaning you are born with it, or they can develop later on, known as acquired lipodystrophy.

Genetic (inherited) lipodystrophy

There are two main types of genetic/inherited lipodystrophy:

Congenital generalized lipodystrophy (CGL)
This is autosomally recessive, meaning you need to inherit two faulty copies of a gene to have it – one from each parent. It’s caused by problems with the AGPAT2 gene or the BSCL2 gene.
Familial partial lipodystrophy
This is autosomally dominant, meaning you only need to have one faulty copy of a gene – from one parent – to have this type. It’s caused by faults in the LMNA gene or the PPARG gene.

Acquired lipodystrophies

There are three main types of acquired lipodystrophy:

Acquired generalized lipodystrophy – a gradual loss of fat from below the skin which begins in childhood or adolescence.
Acquired partial lipodystrophy – a gradual loss of fat from the upper body, which is often linked to autoimmune diseases.
HIV-associated lipodystrophy – this type happens in people with HIV after starting anti-retroviral therapy.

Complications of lipodystrophy

The loss of fat can cause problems with your metabolism – the normal chemical reactions that happen in your body – which can lead to problems such as:

insulin resistance, which can lead to Type 2 diabetes
high triglycerides (a type of fat) in the blood
hepatic steatosis (where triglycerides build up in the liver) which can progress to liver disease (cirrhosis).

How severe these problems are is usually related to how much fat is lost.

How is lipodystrophy treated?

Management of lipodystrophy focuses on preventing and treating the complications above. For example, with medicines to treat diabetes and high blood fats. A healthy diet and exercise are important too.

Find out more

Lipodystrophy UK

Cambridge University Hospitals

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

https://rarediseases.org/rare-diseases/tangier-disease/

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

https://rarediseases.info.nih.gov/diseases/12864/hepatic-lipase-deficiency
https://ghr.nlm.nih.gov/condition/hepatic-lipase-deficiency#definition

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

https://www.ncbi.nlm.nih.gov/books/NBK1409/

If you are worried about your cholesterol, you can email our Cholesterol Helpline

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