What Are Autosomal Recessive Disorders

Autosomal recessive disorders

What is autosomal recessive disorder? To make it easier for you, let’s break down the words. So, “autosomal” means the gene present on the non-sex chromosomes, and “recessive” means two copies of the gene mutated coming from each parent are able to cause a disorder.¹ To understand the basis of genetics, we should first mention Mendelian genetics by Gregor Mendel,  a monk from Austria who worked with garden peas. From his studies,³ laws were established:

1. Law of Segregation - Mentions that each reproductive cell (gamete) will have one allele for a characteristic (trait) and when combined with another reproductive cell, will produce an offspring with a pair of alleles for each trait from both parents.
2. Law of Independent Assortment - This shows that during meiosis and fertilisation, various trait alleles can join and segregate separately from each other. 
3. Law of Dominance - Suggests that one allele is more e dominant than the other one and, therefore, will conceal the other allele. The concealed allele would be known as the recessive allele.²

Prevalence and impact

Autosomal recessive disorders are known to be a burden. This is because studies have shown that it affects around 1.7-5 in 1000 infants, whereas autosomal dominant disorders affect around 1.4 in 1000 infants. Nonetheless, studies have shown that the prevalence is greatly higher in populations with increased levels of consanguinity (descending from the same ancestor) or in combination with endogamy (in-breeding).³

Mechanisms 

Diseases that are transmitted from autosomal recessive patterns will be shown when an individual inherits both recessive alleles, resulting in the individual being affected by the disease. According to the first Mendel law of segregation, this would mean two parents should at least have one of the alleles that would be passed to their child. The easiest way to determine the pattern of inheritance is to look at the pedigree. To be considered an autosomal recessive pattern, it should skip generations because individuals who are affected will have parents who are unaffected carriers.²

It is common for these diseases to occur when the parents are carriers (heterozygous) Dd. Thus, the children of these parents would have a 25% (1 in 4) chance of inheriting the disease. The Punnett square below would show the probability of offspring inheriting the disease. ⁴

• 25% chance  the child is born with two normal genes (DD)

• 50% chance the child is born with a normal and an abnormal gene, so is a carrier (Dd)

• 25% chance the child has mutated genes (dd)

Common autosomal recessive disorders

There are several common diseases caused by an autosomal recessive mutation:

Cystic fibrosis

Cystic Fibrosis is an autosomal recessive disease which is known to affect a particular protein in the body. It is caused by a mutation in the CFTR gene that is found on chromosome.⁷ This disease is commonly known to occur in individuals of caucasian descent, affecting 1 in 1000 births, with 1 in 30 people being carriers of the disease.² Individuals affected with cystic fibrosis will produce abnormally sticky and thick mucus, which causes blocking and harm to various body organs. Resulting in the disturbance of the function of the lungs, leading to chronic infection. It can also affect the pancreas, salivary and sweat glands, being unable to secrete chloride on the surface of the cells. Other issues also include infertility because of a decrease in the absorption of nutrients, which can cause damage to the reproductive system. Currently, no cure is available for this disease. However, different techniques and medications can be used for better management of the disease, for instance, antibiotics for the treatment of chest infections and lung transplant for when lungs have been seriously damaged.^{5, 6}

Sickle cell anaemia

Sickle cell anaemia is also a common autosomal recessive disease that is mainly found in African Americans, accounting for 1 in 365 newborns to have this disease and 1 in 13 would be carriers of the disease. Sickle cell anaemia causes a mutation in the HBB gene. Sickle cell anaemia includes an oxygen-carrying protein called haemoglobin found in red blood cells. Normal red blood cells are often round, flexible and smooth, like a doughnut in shape, allowing a higher surface area for oxygen to be carried and for the ease of transport within the blood vessels. However, sickle cells are sticky, stiff, and banana-shaped, so they often lose oxygen. Thus, they cluster together and don't move easily in a blood vessel, resulting in the stopping of the healthy movement of the haemoglobin. Normal haemoglobin cells can survive for 120 days, and sickle cells, unfortunately, only for 15 days, so due to the decrease of haemoglobin in the blood, the individual may be chronically anaemic. A risk that is found in patients with sickle cell anaemia is the malfunction of the spleen, as well as extreme pain, swelling, frequent infections, vision impairment, and shortness of breath. Treatments to better manage these symptoms include managing diet, medication, blood transfusions, and/or stem cell transplants for severely affected individuals.^{2, 7}

Tay-sachs disease

Tay-Sachs disease is commonly found in European Ashkenazi Jewish, accounting for 1 in 27 individuals. It affects children aged 5 and is caused by a mutation in the HEXA gene, thus causing the absence of the hexosaminidase A protein in the lysosomes of the cells. This absence leads to the build-up of lipids in the brain, resulting in damage to the brain and spine. Currently, no cure is available, and it can only be found a few months after the birth of the affected newborns, so supporting treatment, like genetic testing, can be provided for better management of symptoms.² 

Diagnosis 

The diagnosis of these autosomal recessive disorders can be important not only for the individual with the disease but also for the family as it helps to recognise their own genetics. Some of the diagnoses can be made as early as during pregnancy with blood tests or right after birth through genetic screening programs. This would help the parents to identify the early signs and symptoms and also understand the importance of an early diagnosis, as this can affect not only the lifestyle of the patient but also future generations. Other more common diagnoses include the use of genetic testing, in particular DNA sequencing, to understand the mutation and carrier testing so that the parents can see the probability of their offspring having an autosomal recessive disease. ⁸ 

Management and treatment

There are different ways in which autosomal recessive disorders are managed and treated. To this day, there is no cure for almost all autosomal recessive disorders, however there are ways in which professionals can help not only the individual with the disease but also the family. Some of these include supportive care, where hospitals can help to better manage the symptoms of these disorders, such as antibiotics and medication. This would help in improving the quality of life because changes in diet as well as various therapies would also be an option.   

More recently, there are newer emerging therapies which can also help the individual, gene therapy being one of them. This can help because it would try to modify the DNA in different ways, such as molecularly “cutting” the DNA or introducing the normal DNA to the body. Another emerging therapy would be enzyme replacement therapy, where the affected enzyme is replaced with a normal enzyme, and it is used to treat enzyme deficiencies. Professionals can also provide the affected individual and their families with psychological and emotional support through coping strategies and family counselling. ^{9, 10}

Prevention and genetic counselling

There are various ways to prevent autosomal recessive disorders, and having genetic counselling is an option for these types of disorders. If you are thinking of starting a family and know or want to know if you have any type of genetic disease, then you can get carrier screening, which involves the parents (mother and or father) providing a sample of blood, saliva or tissue to detect if you carrying any particular genetic disease. If you are pregnant, then one way to test would be through prenatal testing; this would allow the mother to know if their baby has any genetic mutations. These would be conducted after 10 weeks of pregnancy.¹¹ 

For those who are considering having a family and do know their family history, then other options may also be available, such as reproductive options. These would be through IVF from a donor or by prenatal adoption. This would go hand-in-hand with informed decision-making because it would provide the family with necessary information and understanding in terms of the disorder and how it can be helped.¹²

Research and future directions

Ongoing research is always present when understanding genetics and autosomal disorders. Currently, a lot of research has been done on the use of CRISPR-Cas9, which is a tool that is used in DNA, particularly for genome editing. So, what does this mean? This means it is a technology that edits the gene by cutting the DNA and allowing the DNA to heal naturally and repair itself through the DNA repair processes. However, with advantages, there are also disadvantages. This technology has shown low success rates and an increased number of non-targeted mutations, which were caused by CRISPR-Cas9 acting abnormally in other parts of the DNA. Targeted therapy is also being used, as it can help through gene supplementation, which helps by delivering a foreign gene to repair and restore the DNA. 

Without the help of international research initiatives, this research and approach would not have been possible. One of these is the Rare Diseases Clinical Research Network, which works to advance medical research through clinical studies.¹³

Summary

Autosomal recessive disorders happen due to genetic mutation, and 3 of the most common disorders affecting the population are cystic fibrosis, sickle cell anaemia, and tay-sachs disease. Though there is no cure for these, there must be early detection and prevention, as some of the symptoms may be managed at an earlier stage. There are ongoing efforts to understand the genetics and research on the treatment of autosomal recessive disorders.