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The Genetics of Spinal Muscular Atrophy

Many families want to learn more about the genetics that have led to Spinal Muscular Atrophy in their family. They want to better understand the condition, what it means for future pregnancies and for other family members, and what genetic treatment options might be available in the future.

Spinal Muscular Atrophy (SMA) is the name given to a number of genetically distinct conditions which all result in muscle weakness, but there is great variation in the severity and impact they can have. All forms of SMA are passed from parents to their children through their genes, making it a hereditary condition.  The genetics of SMA is though complex and every person with SMA is different. You can always ask your child’s medical team to go over any of this information with you.  They should be able to provide you with genetic information that applies to your individual situation. This information sheet covers the genetics of childhood onset SMA Types 1, 2 and 3 and adult onset SMA Type 4. These SMA Types are all caused by recessive mutations in the SMN1 gene (explained fully later). We hope it will be useful for individuals, their families, healthcare and other professionals. 

There are other 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).

What are genetic conditions?

Genetic conditions are caused by differences or '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.

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 structure of the protein, and therefore its 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, which determine your sex. Females usually have two X chromosomes (XX), and males 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 equally.  

We all carry some faulty genes. However, in many cases, carrying a second healthy copy of the same gene can compensate for this. In a recessive condition (like SMA Types 1, 2, 3 or 4), a person who carries one faulty copy of the gene and one healthy 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 fifth autosomal chromosome3 and a person will only develop SMA if they inherit two faulty copies of the SMN1 gene

What is a carrier?

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

It is estimated that as many as 1 in 40 people may be a carrier of SMA4. 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. Your child’s medical team should 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

For each pregnancy, the chances are:

  • Child won't have SMA and won't be a carrier: 1 in 4 chance (25%)
  • Child won't have SMA but will be a carrier: 2 in 4 chance (50%)
  • Child will have SMA: 1 in 4 chance (25%)


Autosomal recessive family 2: One parent is a carrier, the other doesn't have SMA and is a non-carrier

For each pregnancy, the chances are:

  • Child will have SMA: not possible (0%)
  • Child won't have SMA and won't be a carrier: 2 in 4 chance (50%)
  • Child won't have SMA but will be a carrier: 2 in 4 chance (50%)


Autosomal recessive family 3: One parent has SMA, the other doesn't have SMA and isn't a carrier

For each pregnancy, the chances are:

  • Child will have SMA: not possible (0%)
  • Child won't have SMA and won't be a carrier: not possible (0%)
  • Child won't have SMA but will be a carrier: 4 in 4 chance (100%)


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

For each pregnancy, the chances are:

  • Child won't have SMA and won't be a carrier: not possible (0%)
  • Child will have SMA: 2 in 4 chance (50%)
  • Child won't have SMA but will be a carrier: 2 in 4 chance (50%)


Autosomal recessive family 5: Both parents have SMA

For each pregnancy, the chances are:

All the children will have SMA (100%).

We don’t have SMA ourselves, but have had one child with SMA. How can we find out if our next child will also have SMA?

Referral to Clinical Genetics Service for genetic counselling (discussed below) is important to obtain advice specific to your own circumstances. If you have already had one child with SMA but don’t have SMA yourself, the most likely scenario is that you and your partner are both carriers of the faulty gene that causes SMA. In this case, if you have another pregnancy together, the chance that your next child will have SMA would be 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. 

You can read information about these options in SMA Support UK’s information sheet Future Options in Pregnancy. You can also discuss what is possible with your healthcare professionals who should be able to help you make this very personal decision.

What is genetic counselling?

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

Genetic counselling is with a healthcare professional who has expert training in genetics. They will answer any questions you have about your genetic circumstances, arrange any further genetic testing that may be necessay and will provide you with advice and information. 

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 have the option to ask for genetic counselling to obtain more information, and to have carrier testing if they wish to do so.. This can be particularly relevant if they are considering a pregnancy in the future.

More information about the genetics of SMA Type 1, 2, 3 and 4

What should the SMN1 gene3 do?

The nerve cells called lower motor neurons run from the spinal cord to the muscles. These lower motor neurons carry electrical signals from the brain to move the muscles used for crawling and walking. These signals also control movement of arms, hands, head and neck as well as breathing and swallowing. For these lower motor neurons to be healthy, our Survival Motor Neuron 1 (SMN1) genes must produce enough Survival Motor Neuron (SMN) protein3. Most people have two copies of the SMN1 gene.

What happens when copies of the SMN1 gene are faulty?

People with one faulty copy of the SMN1 gene (carriers) are able to produce enough protein to keep their lower motor neurones healthy and so do not have symptoms of SMA. People with two faulty copies are unable to produce enough SMN protein to have healthy lower motor neurons. The  result is a progressive deterioration and loss of lower motor neurons5-7. Movement is weaker,  due to impairment in the delivery of signals from the brain to their muscles.. A lack of stimulation from nerves and movement also causes muscle wasting; this is known as muscle atrophy.

The SMN1 gene lies on the fifth chromosome in the region labelled ‘q’. This is why SMA Types 1, 2, 3 and 4 are often referred to as ‘5q SMA’. 

I’ve heard about deletion and point mutations in the SMN1 gene, what are they?

A deletion describes a type of mutation or fault when a small section of DNA is missing. When part or all of a gene is missing, it can no longer make healthy protein. Instead, a shorter, often less functional (less useful) protein is made, or in some instances no protein at all.

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, these people will have the more common deletion mutation in one of their copies of SMN1 and the point mutation in the other copy.

In most cases, mutations in SMN1 are inherited from a parent who is a carrier. In around 2% of cases of SMA however, the mutation is new in the affected person, most likely due to an error in making the egg or sperm cell from which they were conceived.  This is called a de novo mutation.  This can have implications for the chance of SMA affecting a future pregnancy, and so emphasises the importance of gaining genetic counselling specific to your own circumstances.      

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

How is the SMN2 gene3 involved?

In addition to SMN1 we possess a second gene that can produce SMN protein. This is the Survival Motor Neuron 2 gene (SMN2) gene, sometimes referred to as the SMA ‘back-up’ gene.  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 functional8.  

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 from7.

SMN2 copy number

Unlike most genes, the number of copies of SMN2 on each chromosome can vary from one person to the next (from 0 – 8 copies)9.

The severity of a person’s SMA has been linked to how much SMN protein a person makes10-12. Therefore, there is a broad relationship between the number of SMN2 copies a person carries (“SMN2 copy number”) and the likely severity of their symptoms. Carrying more SMN2 copies is generally associated with less severe SMA symptoms. However, accurate predictions cannot be made about the type or severity of SMA based on the SMN2 copy number alone.  This is likely to be because other genetic factors also have a modifying influence.

Although SMN2 copy number is not essential for an SMA diagnostic or carrier testing, it is often collected and recorded as part of the diagnosis. This is because it is often used in clinical trials to group patients to try to identify whether copy number affects the effectiveness of the drug being tested. However, as SMN2 copy number and SMA severity do not correlate perfectly, the results do have to be treated with caution.

Possible treatments addressing the genetics of SMA Types 1,2 and 3

There is extensive research into the genetics of SMA and the underlying mechanisms that lead to damage of the nerve cells. The UK is a significant contributor to this, with several UK centres involved in clinical trials and international collaborations. This has led to encouraging breakthroughs in developing treatments.

  • Nusinersen/ SpinrazaTM   

The first (and currently, the only) potentially available treatment for SMA is called nusinersen. Essentially the drug targets the SMN2 gene to produce more SMN protein. In collaboration with researchers, nusinersen was developed by Ionis Pharmaceuticals and Biogen Idec, which have run clinical trials with infants and children affected by SMA Types 1, 2 or 3. There have not yet been any clinical trials of nusinersen with anyone with SMA Type 4.

On June 1st 2017, the European Commission approved nusinersen for marketing under its brand name SpinrazaTM as a treatment for those with 5q SMA13. This includes SMA Types 1, 2, 3 and 4. 

To find out more about nusinersen and any updates on access to this treatment in the UK, please go here.

  • Other developments

The UK SMA Patient Registry is a database of genetic and clinical information about people affected by SMA. As new treatments for SMA are being developed, they need to be tested in clinical trials. Researchers wanting to find people interested in joining a clinical trial contact the Patient Registry which then contacts the people who have registered to let them know about the potential opportunity. If this is of interest to you, you can sign up with the Patient Registry.

The Registry also helps specialists gain more knowledge about the condition and the number of people affected by SMA. This information helps to develop and improve worldwide standards of care for people with SMA. For more information see ‘Further information and resources’ at the end.

SMA Support UK’s website also notifies the SMA community about latest developments with potential drug treatments, the science behind them and what clinical trials and other research is going on. Please go to our research section. We alert people to updates via our social media and monthly E- news. You can sign up for mailings here

Other common genetics-related 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, you can still seek genetic counselling if you are already pregnant – just make sure to say you are pregnant and ask to be seen urgently.   

 

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 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.

 

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 can take 6 - 8 weeks to test for a known family alteration or common gene change. It may take longer for rarer types of SMA. Testing can be completed more urgently in certain situations (for example, in pregnancy or a very unwell baby). 

 

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:

Genetic Alliance UK                  Tel: 0207 704 3141

Clinical trials information:

How clinical trials work

Current clinical trials in SMA: www.clinicaltrials.gov/

The UK SMA Patient Registry: www.treat-nmd.org.uk/registry

 

If you have any feedback about this information, please do let us know here

Version 2.1
Author: SMA Support UK Information Production Team 
Last updated: June 2018
Next full review due: February 2021
 

 

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References

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  12. UK North Star and SMA-REACH clinical networks and SMA Support UK, TreatSMA and SMA Trust (2017) Letter to Edmund Jessop, 23 August. Available at: www.smasupportuk.org.uk/files/files/Research/August%2017/
    Nusinersen%20letter%20August%202017.pdf

     
  13. European Medicines Agency (2017) ‘Committee for Medicinal Products for Human Use Assessment Report Spinraza’ (EMA/289068/2017). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004312/WC500229706.pdf (Accessed: 9 February 2017)