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The Genetics of Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a hereditary condition that is passed from parents to their children through their genes. When faced with a diagnosis of SMA many families want to learn more about genetics so that they have a better understanding of the condition, what it means for future pregnancies and for other family members, and what genetic treatment options might be available in the future.

This information sheet is for families of children diagnosed with SMA Types 1, 2 and 3 that are caused by recessive mutations in the SMN1 gene (explained fully later). There are other rarer forms of SMA which are not covered in this information sheet, however, some of the information may still be useful. (You can also read the SMA Support UK leaflet ‘The Genetics of Some Rarer Forms of Spinal Muscular Atrophy’)

The genetics of SMA is complex and every person with SMA is different. Your medical team will always be happy to go over any of this information with you and they can provide you with genetic information that applies to your individual situation.

As well as families, this information may also be useful for healthcare and other professionals, and members of the general public. 

What are genetic conditions?

Genetic conditions are caused by faults in our genes.

Our bodies are made up of many millions of cells. Nearly all cells have a structure called the nucleus, which contains chromosomes.

Body cells usually have two copies of each chromosome – one inherited from a person’s mother and the other one from a person’s father.

We all have 46 chromosomes in each cell in our body and these are arranged in 23 pairs.

Chromosomes are compact bundles of DNA. (See Box 1 below for an explanation of DNA.)

A gene is a specific section of DNA. Genes are packaged into chromosomes.

Genes carry the information needed to make proteins. Our cells need protein for their structure, survival and to work correctly. We each have approximately 20,000 different genes making different proteins in our bodies1-2. Each protein made by a different gene has its own unique function. The function is determined by the order in which the base pairs are arranged in that particular gene. Usually there are two copies of each gene on each chromosome pair: one inherited from each parent.

Sometimes a gene can contain an unusual change or fault known as a mutation. Genetic conditions occur when a mutation within a gene affects how the protein in our bodies is produced and how it works. 

Box 1 – an explanation of DNA

DNA is often described as a recipe book, or a set of instructions, because it contains the information need for a person to grow and develop.

DNA is made up of lots of nucleotides joined together. Each nucleotide contains a phosphate, a sugar and a base. The phosphate and sugar are always the same but the base varies in each nucleotide. The base can be one of four: adenine (A), guanine (G), cytosine (C), or thymine (T).

These bases pair up: A with T, C with G. The order in which these pairs of bases are arranged affects how the ‘recipe book’ information is read. The joined base pairs hold the nucleotides together in strands that twist together to form the DNA double-helix shape. 
 


SMA is an autosomal recessive condition - what does that mean?

People have 23 pairs of chromosomes. 22 of the pairs are non-sex chromosomes, known as autosomes, and they are found in both males and females. The 23rd pair consists of two sex chromosomes (X and Y), which determine your sex. Females have two X chromosomes (XX), and males have an X and a Y chromosome (XY).

Conditions described as autosomal are those in which the faulty gene (mutation) that causes the condition is located on one of the autosomes and not on one of the two sex chromosomes. Autosomal conditions affect both males and females.  

We all have some faulty genes. In a recessive condition (like the main types of SMA), a person who carries one faulty copy of the gene and one normal copy will not have the condition.

SMA is an autosomal recessive genetic condition because the Survival Motor Neuron 1 (SMN1) gene responsible for SMA is located on the autosomal chromosome 53 and you must have two faulty copies of the gene for you to have SMA.

What is a carrier?

In a recessive condition, people who have one healthy copy and one faulty copy of a gene do not have any symptoms, but the faulty gene can be passed on to their children. As a result of this they are called carriers.

It is estimated that as many as 1 in 40 people may be a carrier of SMA4-7. When two carriers have a child together there is a chance that their child will have SMA or will be a carrier. Each copy of the gene (healthy or faulty) has the same chance of being passed on. This happens randomly, like the result of a coin toss.

What are the chances that my children will have SMA or be carriers?

The chances of your children being carriers or having SMA will depend on whether you or your partner have SMA or are carriers. The chances stay the same for each pregnancy. Having one child who has SMA or is a carrier does not change the chances for any further children. The following diagrams show what the chances are in different families. For the purpose of the diagrams a ‘non-carrier’ means a person who does not carry the faulty gene and does not have SMA.

Please remember that if your child has a rare form of SMA the diagrams may not necessarily apply to you and your family. If this is the case your child’s medical team will be able to give you information about your particular genetic situation. You can also read SMA Support UK’s leaflet ‘The Genetics of Some Rarer Forms of SMA’.


Autosomal recessive family 1: Both parents are carriers

If two carriers have a child together the chances are as follows:

  • Child does not have SMA and is not a carrier: 1 in 4 chance (25%)
  • Child does not have SMA but is a carrier: 2 in 4 chance (50%)
  • Child has SMA: 1 in 4 chance (25%)


Autosomal recessive family 2: One parent is a carrier, the other does not have SMA and is a non-carrier

Their child will not have SMA but they could be a carrier.

  • Child has SMA: not possible (0%)
  • Child does not have SMA and is not a carrier: 2 in 4 chance (50%)
  • Child does not have SMA but is a carrier: 2 in 4 chance (50%)


Autosomal recessive family 3: One parent has SMA, the other does not have SMA and is a non-carrier

Their child will not have SMA but they will be a carrier.

  • Child has SMA: not possible (0%)
  • Child does not have SMA and is not a carrier: not possible (0%)
  • Child does not have SMA but is a carrier: 4 in 4 chance (100%)


Autosomal recessive family 4: One parent has SMA, the other is a carrier

Their child will be either be a carrier or have SMA.

  • Child does not have SMA and is not a carrier: not possible (0%)
  • Child has SMA: 2 in 4 chance (50%)
  • Child does not have SMA but is a carrier: 2 in 4 chance (50%)


Autosomal recessive family 5: Both parents have SMA

All their children will have SMA.

We have had one child with SMA, how can we find out if our next child will also have SMA?

If you already have had one child with SMA then we assume that you and your partner are both carriers of the faulty gene that causes SMA. If you have another pregnancy with the same partner the chance that your next child will have SMA is 1 in 4 (25%), as shown in the autosomal recessive family 1 diagram. The copy of each gene inherited from each parent is random and cannot be predicted. Some couples who are both carriers decide to take that chance while others want to consider alternative options when having children.

One option is prenatal diagnosis, for example amniocentesis or Chorionic Villus Sampling (CVS). If the test shows that the foetus does have SMA then the couple will have the opportunity to decide whether or not to continue with the pregnancy. Another option is pre-implantation genetic diagnosis (PGD), which involves collecting eggs from the woman and fertilising them outside the body (similar to IVF treatment). Each embryo is tested and only embryos that are carriers or do not have SMA are implanted back into the uterus. A new option, available from September 2016 is Non-Invasive Prenatal Diagnosis (NIPD) which tests the foetus’ DNA in a blood sample from the mother.

As a couple you will want to make a joint personal decision about these options and the healthcare professionals who see you will give you more information to help with this. You can also read SMA Support UK’s information sheet ‘Future Options in Pregnancy’:   

What is genetic counselling?

If you have a child with SMA you should be offered a referral for genetic counselling. You can also request a referral from your General Practitioner (G.P.).

Genetic counselling takes place with a healthcare professional who has expert training in genetics. They will answer any questions you have regarding your genetic circumstances and they will provide you with advice and information. You will be able to go back to them at a later date if you have more questions.

Adults with SMA can also ask for genetic counselling, particularly if they are considering having children.

I’m a carrier, should I suggest that other family members get tested?

As genes are inherited from parents and passed on from generation to generation you share many of your genes with members of your extended family. It is therefore possible that your blood relations may also be carriers of the same faulty gene. You might want to tell your relations about this so that they can make their own decisions about testing. They should also have the option of genetic counselling so that they can obtain information for themselves and make a decision about whether they want to have carrier testing.

More information about the SMA mutation:

What does the mutation that causes SMA do?

People who have SMA have a fault in a gene called Survival Motor Neuron 1 (SMN1)3. SMN1 is found on chromosome 5 and is responsible for making an essential protein called the Survival Motor Neuron (SMN) protein. SMN protein is found in all the cells in your body and is particularly important for nerve cells called lower motor neurons8-10. These connect your brain and spinal cord to your muscles allowing you to contract your muscles so that you can move. When SMN protein levels are reduced past a certain point the lower motor neurons deteriorate causing muscle weakness and atrophy (wasting).

Carriers of SMA have one normal copy of the SMN1 gene. This is usually sufficient for their bodies to make enough of the SMN protein for them to live without the symptoms of SMA. However, people who have inherited two faulty copies of SMN1 cannot make enough SMN protein and so they have SMA.

What is a deletion?

A deletion is a type of mutation that involves the removal of a small section of DNA. When part or all of a gene is missing your body can no longer make healthy protein. Instead, a shorter, often less functional protein is made or in some instances no protein at all is made. About 95% of people with SMA have a deletion mutation in both copies of the SMN1 gene. This is called a homozygous deletion.

The other 5% of people with SMA have a point mutation. This is when a single base (nucleotide) within the DNA is altered. Often they will have the more common deletion mutation in one of their copies of SMN1 and the point mutation in the other copy. Point mutations in SMN1 can be inherited from a parent or arise as new mutations (called de novo mutations), meaning that they have occurred accidentally in the parental egg or sperm that made that particular person. There is then the chance that that person will pass the condition on to their own children. 

Figure 1. Deletion and Point Mutations. Taken from Skirton. H. and Patch, C. (2009) Genetics for the Health Sciences. Oxford: Scion Publishing.

What is the SMN2 gene?

In addition to SMN1 we possess a second gene that is able to produce some functional SMN protein. This gene is almost identical to SMN1 and is therefore called the SMN2 gene3. SMN2 has an important single base (nucleotide) difference from SMN1. This causes a small chunk of the gene, called Exon 7, to be excluded in the majority of SMN protein that the SMN2 gene makes. It is estimated that only about 10% of the SMN protein made from SMN2 is functional11

Figure 2. People possess two genes able to produce SMN protein. SMN1 produces all the functional SMN protein we need and is the gene affected in SMA. SMN2 only makes a small fraction of functional protein (about 10%). The large majority (about 90%) of protein produced from SMN2 is lacking an essential part and is consequently non-functional. Figure adapted from 10.

SMN2 copy number

Usually we all have two copies of each gene, one inherited from each parent, on each chromosome pair. However, sometimes duplication happens resulting in some people having more than the usual one copy of SMN2 on each chromosome.

The severity of a person’s SMA is dependent on how much functional SMN protein their SMN2 gene produces. The higher the copy number (i.e. the more copies of the SMN2 gene), the less severe their SMA is likely to be12-13.

Individuals with fewer copies of SMN2 will on average produce less functional SMN protein and are therefore more likely to develop a more severe form of SMA. However, SMN2 copy number cannot be used to determine the Type of SMA an individual will have as other genes and differences in the SMN2 gene itself can affect how much SMN protein is made. For example, an individual with two copies of the SMN2 gene could have SMA Type 1 or SMA Type 2.

As SMN2 copy number analysis is not predictive for individual cases it is not performed for diagnostic or carrier testing purposes for SMA. It is, however, often used in clinical trials to group patients in order to try to identify whether copy number affects the effectiveness of the drug being tested. As SMN2 copy number and SMA severity do not correlate perfectly the results do have to be treated with caution.

Types of SMA

The varying amounts of SMN protein that can be produced from the SMN2 gene means that there is a wide range in the severity of SMA. For more information on the different types of SMA please see SMA Support UK’s individual information sheets for SMA Types 1, 2, 3, 4 and SMARD. These can be downloaded from the website here or requested by phone on 01789 267 520 or by e-mail: supportservices@smasupportuk.org.uk

Rarer forms of SMA

As previously stated this information sheet focuses on SMA caused by recessive mutations in the SMN1 gene. There are other rarer forms of SMA, some of which are covered in the SMA Support UK leaflet ‘The Genetics of Some Rarer Forms of Spinal Muscular Atrophy’. You can also ask your medical team if you require further information on any of the rarer forms of SMA.

Possible treatments for SMA

There is extensive research taking place into the genetics of SMA. Alongside improved understanding of the condition this has led to the development of potential treatments. Some of these are being tested in clinical trials and may potentially be licensed in the UK.

For information and the latest updates on current clinical trials please see the web links in the further information and resources section of this leaflet.  

SMA Support UK notifies the SMA community of the publication of any research updates and developments via its website, social media and monthly E-news. You can sign up for mailings here.

 

Common questions

Q: My partner is a carrier of SMA and we are thinking of having children. Where can I get tested to see if I am a carrier too?

A: Ask your General Practitioner (G.P.) to refer you to your regional genetics centre. The main genetics clinics are usually in large regional cities, but outreach clinics may be held in other smaller hospitals across the region.

 

Q: In a family with SMA who will be able to have genetic testing?

A: Staff at your regional genetics centre can give you specific advice about who might need to be tested. Close family members will be seen first to identify who might be carriers. The process might include drawing a family tree.

 

Q: There is a history of SMA in my family, when should my partner and I have genetic testing?

A: Having genetic counselling before pregnancy will give you and your partner more time to think about genetic testing and the possibly difficult decisions this can raise. But, do not be afraid to seek genetic counselling if you are already pregnant. 

 

Q: What is the waiting time for a genetics appointment?

A: You will usually be offered an appointment within 18 weeks.

 

Q: A member of my family has been diagnosed with SMA. I am pregnant and I don’t know if I am a carrier. How do I get a quick referral to genetic services?

A: Contact your General Practitioner (G.P.) to ask for an urgent genetic counselling referral. If this is not possible you can contact your local genetic service directly (a list of centres is available on the British Society for Genetic Medicine website). You and your partner may be offered testing if appropriate.

 

Q: I have no family history of SMA, can I still be tested?

A: Genetic testing is not usually available on the NHS to people with no personal family history or connection to SMA.

 

Q: Can I have a genetic test for SMA without having genetic counselling?

A: This is generally not possible via the NHS. Genetic counselling will give you the most up-to-date and accurate information enabling you to make informed choices about the options available to you.

 

Q: How long will it take to get the results of a genetic test for SMA?

A: It usually takes 1 to 2 months to test for a known family alteration or common gene change. It may take longer for rarer types of SMA.

 

Q: How many copies of the SMN2 gene can an individual have?

A: Theoretically quite large numbers are possible, but highly unlikely. It has been reported that some individuals have 4-8 copies of the SMN2 gene but 1-2 copies is more usual.

 

Q: I have been tested for SMA and the test has come back negative but my consultant still thinks I have SMA. Is this possible?

A: In a small number of cases the genetic basis is more complex and further genetic testing may be necessary. Your doctor will advise you depending on your symptoms and the tests you have had so far.

 

Q: My son has SMA symptoms but the test has come back negative. Is it possible that he has SMA? 

A: Routine testing for SMA will confirm the diagnosis in the majority of people but sometimes further genetic testing may be needed. Your doctor will advise you depending on your son’s symptoms and the tests he has had so far. This may include investigations for other conditions that can present in a similar way to SMA.

 

Q: My daughter has been diagnosed with SMA. I’m worried that her brother and sister might develop SMA too. Should they be tested?

A: It is important for you to discuss this with the healthcare professionals involved and your family. Your decision may be influenced by the type of SMA your daughter has and whether you already have worries about the health of your other children.  

 

Q: My sister’s son has been diagnosed with SMA. I have a 4 year old daughter and I’m worried that she might develop SMA too. Should I have her tested?

A: You could have carrier testing at a genetic centre to see whether or not your children have a chance of having SMA. Once you have your result you can discuss with your healthcare professionals and your family whether or not to test your daughter. Genetic centres would not usually offer carrier testing in childhood as it removes the child’s right to make an informed decision when they are older.

 

Further information and resources

Genetics and Genetic Testing

Cure SMA (America) (formerly Families of SMA)

Genetic Alliance UK                  Tel: 0207 704 3141

 

Pre-implantation Genetic Diagnosis (PGD) information

Genetic Alliance UK                  Tel: 0207 704 3141

SMA Support UK - Future Options in Pregnancy

 

Clinical trial process information

TREAT-NMD - Neuromuscular Network information about clinical trials and research. TREAT-NMD can be contacted on: 0191 241 8605.

Clinical Trials.gov - American website which explains what clinical trials are.

Cure SMA - American website for families, formerly called Families of SMA.

 

Current clinical trials in SMA

TREAT-NMD is a network for the neuromuscular field that provides an infrastructure to ensure that the most promising new therapies reach patients as quickly as possible. Current SMA trials are listed on their website hereTREAT-NMD can also be contacted on: 0191 241 8617.

Clinical Trials.gov – American website which lists SMA clinical trials.

 

Research Progress

SMA Support UK:

General research overview

Drug treatments - what's happening now?

 

The UK SMA Patient Registry

The Patient Registry is a database of genetic and clinical information about people affected by SMA. It is used to find participants for clinical trials and to help specialists gain more knowledge about SMA. Information about the work of the Registry and how to sign up can be obtained from SMA Support UK or downloaded hereThe registry can also be contacted on: 0191 241 8605.

 

Version 1.6
Author: SMA Support UK Information Production Team with Rachel Thompson, SMA Patient Registry Curator 2012-2013, and Dr James Sleigh, SMA Support UK Research Correspondent
Published: September 2014
Reviewed: January 2017
Full review due: September 2017

 

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