HEREDITARY DISEASES

Did you know that we can pass on genetic disorders to our children, even if we do not suffer from them ourselves? In fact, we only need to be carriers to pass them down our offspring. In other words, even if we have not developed symptoms, if we are carriers, our children are at risk of inheriting the disorder. We can also develop hereditary diseases if an error occurs during foetal formation; these are the cases where the parents are not carriers. 

In the post “Diseases and types of genetic inheritance” we explain the different ways people inherit diseases in more detail. In this article we look at several examples of hereditary disorders and how they can be passed on through generations.

What is a hereditary genetic disorder?

A genetic disorder occurs when one or more genes are altered

If this genetic alteration is passed on to offspring, then it is a hereditary genetic disorder. 

Therefore, we should clarify that not all genetic disorders are hereditary, since they are often not passed on to children.  

For a genetic disorder to be inherited, the altered gene must be found in the germline cells of the affected individual. In other words, in the eggs or in the sperm cell; that is why the genetic combination of the biological parents is influential when it comes to passing on diseases to our children.

The difference between hereditary and congenital disorders

Hereditary disorders do not necessarily present symptoms from birth. However, congenital ones do. 

With the information we have provided so far, we can make these distinctions:

  • Genetic disorders: these are the result of the alteration of one or more genes and may or may not be hereditary.  
  • Hereditary disorders: these all have a genetic origin, i.e. they are the result of the alteration of one or more genes and are passed on through generations. Symptoms may not necessarily present themselves from birth. 
  • Congenital disorders: these can be hereditary or not, and in these disorders, individuals present symptoms from birth.  

Examples and symptoms of some hereditary disorders

Achondroplasia

Our first example of a hereditary disease is achondroplasia. In this disorder, the cartilage does not develop normally, which is why sufferers are characterised by their short limbs, macrocephaly and short stature, which generally reaches 130cm in men and 124cm in women.

This is a hereditary congenital disorder, i.e. its symptoms are noticeable from birth. 

Although the disorder does not affect intellectual development at all, motor skills may develop more slowly. The prognosis for the disease is good, and people with achondroplasia have a normal life expectancy, which will only be slightly shorter if they have cardiovascular disease.  

Involved gene and inheritance pattern 

The cause of 97% of achondroplasia cases is related to mutations in the FGFR3 gene, which is linked to the regulation of linear growth of long bones.

As for the inheritance pattern, it is autosomal dominant, i.e:

  • If only one parent has the disease, there will be a 50% chance of passing the disease on to the baby in each pregnancy. 
  • If both parents have achondroplasia, there can be very serious implications if their offspring inherit the two altered copies of the gene. If this happens, they will develop a very severe form of the disorder that could be fatal to the baby before or after birth. 

Although achondroplasia is hereditary, and if parents have it, they can pass it on to their children, in 80% of cases it is caused by “de novo mutations”, i.e. mutations that occur spontaneously during embryo development and are therefore not inherited from the parents.  

Marfan syndrome

This is another hereditary disorder which affects connective tissue, mainly the blood vessels, heart, eyes and skeleton.  

Connective tissue supports, protects and helps to form various tissues and organs such as blood vessels, organs, muscles and even skin, among others. It also contributes to our body’s development both before and after birth and also plays a role in cushioning the joints. 

Marfan syndrome symptoms vary from person to person, even among members of the same family, and can range from mild to very severe. 

The most dangerous complications are those that affect the blood vessels and the heart. This connective tissue defect can affect the aorta (the artery that carries oxygen from the heart to the other organs) and can lead to an aneurysm or even a dissection. One of the most serious cardiac complications that can occur is valve malformation. Additionally, bone and eye complications can occur and women should be especially cautious during pregnancy due to the increased risk of aortic rupture or fatal dissection.

Here are the most common Marfan syndrome symptoms: 

  • Tall stature and slim build, with disproportionately long limbs and toes.
  • Curved spine.
  • Sunken sternum or, alternatively, protruding sternum.
  • Arched palate and crowded teeth. 
  • Flat feet.

Although Marfan syndrome has no definitive cure, there are treatments, based on periodic monitoring and pharmacological treatment, that can prevent complications such as those that may occur in the aorta. As for patients’ life expectancy, it has increased from 45 to 72 years thanks to early diagnosis and current treatments. 

Involved gene and inheritance pattern 

The gene linked to this disease is FBN1, which produces a protein that is a structural component of microfibrils. Microfibrils are part of the connective tissue and control the release of growth factors, among other functions. When this gene is altered, the microfibrils cannot carry out their function properly, generating the symptoms described above. 

The inheritance pattern of Marfan syndrome is autosomal dominant, so if a parent has it, they have a 50% chance of passing it on to their children. 

As we saw with achondroplasia, de novo mutations can also occur, which account for 25% of cases of this disorder.

Sickle-cell disease

Sickle cell disease affects the shape of red blood cells and their ability to carry oxygen.  

Normally, red blood cells are round, but in people with this hereditary disease they have a crescent-shaped appearance, causing the red blood cells to stick together, which can lead to a blockage of the small blood vessels. This can cause pain, as well as damage to areas where the blood cannot reach.

Some of the symptoms that sufferers exhibit with this disease are:

  • Anaemia: because these red blood cells have a shorter half-life than unaffected ones. 
  • Pain episodes, which can last for hours or days. 
  • Damage to the spleen, heart, brain, etc. 
  • Swelling of the hands and feet.

Only bone marrow transplantation can cure the disease, but it is only considered in some cases due to the associated complications. 

General treatment focuses on enabling sufferers to lead virtually normal lives and includes penicillin vaccines to prevent infection, folic acid supplements to synthesise new red blood cells, and pain medications. 

Involved gene and inheritance pattern 

An altered HBB gene, essential for generating haemoglobin, is responsible for this disease. Its mode of inheritance is autosomal recessive, so both parents must have an alteration in at least one of the two copies of the gene for it to be a risk factor for the disease. If both parents are carriers, there is a 25% risk that their offspring will have the disease. If one parent has the disease and therefore has two altered copies, while the other parent is only a carrier, the risk of their offspring developing the disease is 50%.

Type 1 hemochromatosis

This disorder causes a build-up of iron because the body absorbs too much of it from food and cannot naturally get rid of the excess. This disorder can lead to excessive iron levels, which are stored mainly in the heart, pancreas and liver and are toxic. 

Symptoms first appear around the age of 50 or 60 in men and 60 in women. This difference is probably due to the fact that more iron is removed by women’s bodies during menstruation and pregnancy.

The most common symptoms of type 1 hemochromatosis are: 

  • Fatigue and weakness.
  • Joint and abdominal pain. 
  • Complications such as liver failure, diabetes, or heart failure. 

Treatment for this disorder is carried out through regular blood draws, to restore iron levels.

There is also medication, injected or in tablet form, to remove excess iron by chelation.

Involved gene and inheritance pattern 

The gene involved is HFE, which produces a protein which helps to detect iron levels in the body. When this gene has a mutation that alters the function of this protein, the cells can not adequately detect these iron levels, so they absorb more iron than they need.

The inheritance pattern is autosomal recessive, so both parents have to have an alteration in one of the two copies of the gene for their child to be affected by this disease.

Colour blindness

This hereditary condition affects the ability to distinguish between the colours green and red or blue and yellow.  

Colour blindness, in most cases, is present from birth, making it a congenital disease. Colour-blind people lead a completely normal life, although the deficiency varies; the most serious form is that in which those affected can only see different shades of grey. 

Involved gene and inheritance pattern 

Some of the genes involved in this deficiency are OPN1LW, OPN1MW and OPN1SW. 

In the case of the first two genes, the inheritance pattern of colour blindness is linked to the X chromosome, so it occurs in 8-10% of men and barely in women, who may be carriers, but usually have no symptoms. However, the third gene associated with colour blindness is not found on the X chromosome and follows an autosomal dominant inheritance pattern. 

Phenylketonuria

A hereditary congenital disorder which disrupts the metabolism of amino acids. Amino acids are the building blocks for proteins. With this disorder, the body is unable to break down the amino acid phenylalanine, so it accumulates in the body.

Symptoms begin to appear a few months after birth, and may include the following:

  • Damp-like odour on the baby’s breath, skin or urine. 
  • Neurological problems, which can include seizures
  • Eczema
  • Microcephaly
  • Developmental delay
  • Hyperactivity

As we can see, some of the symptoms caused by this disorder are serious, but they can be prevented if treated in the first few weeks of the child’s life and if the levels in the body do not build up too much. Management is mainly dietary, with a lifelong low-phenylalanine diet, which is mainly found in higher protein foods.

If you start this diet after birth and strictly maintain it throughout adulthood, the prognosis is favourable, with better physical and mental health than those who do not follow it. It is important to know that the brain damage that will occur can lead to severe mental disability if this diet is not followed early on in life.

Involved gene and inheritance pattern 

This disorder is caused by mutations in the PAH gene, which produces an enzyme essential for the breakdown of the amino acid phenylalanine. These mutations decrease this protein’s performance, causing abnormal levels of phenylalanine that are toxic to the body, especially the brain. 

The inheritance pattern of this disease is autosomal recessive, so as we have seen in the other examples in this article, it needs both parents to carry at least one copy of the altered gene for the disease to occur.

Genetics and environment

All the examples of hereditary diseases we have seen so far are the result of a gene alteration, i.e. they have a genetic origin. However, there are many diseases that have both genetic and environmental risk factors.  The genetic load carries a lot of importance in these cases, but certain circumstances are also needed to trigger the disease.

In these cases, parents pass on the risk of a particular multifactorial genetic disorder to their children. 

Below are some examples.

Diabetes

There are several types of diabetes, including:

  • MODY diabetes: in this case, the onset of the condition only requires a mutation in one of the genes involved. There are different types of MODY, each linked to a different gene. These mutations generally affect the ability for pancreatic beta cells in our body to produce insulin or, impair the body’s detection of elevated blood glucose levels, thus leading to diabetes. 
  • Type 1 diabetes: so many genetic factors are involved in this type of diabetes that increase predisposition to the condition, and environmental factors are what trigger the onset of the condition. In some cases, this diabetes is caused by an autoimmune reaction where our own body attacks the pancreatic beta cells.

Type 2 diabetes is the most common type and is influenced by both genetic and lifestyle factors. Genetic risk is linked to about 150 variants in the DNA.

Myopia

As you may know, myopia is a very common visual disorder. It affects 25% of the Spanish population and it is an hereditary disease.

People with this problem have blurry vision when looking at objects from a certain distance, but not at objects close by, which are clear.  In other words, they see badly from afar. This is due to a focusing problem, which is caused by the eye’s shape, resulting in light being refracted incorrectly in front of the retina rather than on it. 

Treatment involves graduated prescription biconcave lenses, or contact lenses, with the patient’s dioptres. Refractive surgery of the cornea (LASIK) can also correct up to 6 dioptres of myopia. Another surgical procedure involves implanting intraocular lenses, which is mainly considered for people with very high myopia or adults over 50 years of age with presbyopia and/or cataracts.

Involved gene and other environmental factors 

There are about 24 genes that cause various types of myopia. Among them are:  ANTXR2, KCNQ5, LAMA2, PRSS56 

In addition to genetic factors, other factors such as straining your eyes by reading too much at a close range, in poor lighting conditions, or spending too many hours in front of a screen also encourage the development of myopia.  

Can I find out if I have or am a carrier of a hereditary disorder? 

As we have seen, genetics and the development of disorders are intrinsically linked, which is not surprising, since our genes contain the instructions that tell our bodies how to function properly, and if these are altered it is likely that disorders will appear. As we have seen, in many cases, their symptoms first appear throughout adulthood, so we may not even realise that we have a disorder until later in life. 

Veritas offers genetic tests that establish whether you are at risk of developing a disorder, whether you are a carrier, or if you have a family member with cancer or cardiovascular disease. You can find out whether these are due to genetic alterations and whether you have them yourself.  As always, we encourage you to take charge of your healthcare by taking a proactive approach in anticipating the onset of a number of diseases. 

This article is based on the original written by Paula Penedo from the Scientific Department.

@healthqueries.in

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