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 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.

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. It includes questions that families often ask.


What are genetic conditions?

Genetic conditions are caused by a fault in our genes.

Your body is made up of millions of cells. Most cells have a structure called the nucleus, which contains chromosomes. Chromosomes are compact bundles of DNA.

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

DNA is made from long strings of consecutive molecules called bases (nucleotides), which come in one of four different types (A, C, G, or T). The order in which these bases are arranged within your DNA affects how the information it contains is read. A gene is a specific section of your DNA and the genes are packaged into chromosomes. We all have 46 chromosomes in each cell in our body and these are arranged in 23 pairs. One chromosome in each pair is inherited from your mother and the other one from your father.

Genes carry the information needed to make proteins. Your cells need protein for their structure, their survival, and to work correctly. Each protein made from a different gene has its own unique function, which is determined by the sequence of bases (nucleotides) in that particular gene. You will have approximately 20,000 different genes making proteins in your body1-2.

Sometimes a gene can have an unusual change or fault, known as a mutation. Genetic conditions such as SMA occur when a mutation within a gene affects how the protein works.


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 Xchromosomes (XX), and males have an X and a Y chromosome (XY).

Conditions described as “autosomal” are those in which the faultygene (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 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 theSurvival 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 (such as SMA), 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 acarrier. 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.


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 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 in which the foetus is genetically tested to see if it has SMA. If it does, 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.

Each couple must make an individual decision about these options and the healthcare professionals who see you will give you more information.


What is genetic counselling?

If you have a child with SMA you should be offered a referral forgenetic counselling. This will be 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. It is ok if you would like 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 with 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 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 normal, healthy protein. Instead, a shorter (“truncated”), 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 ofSMN1, and the point mutation in the other copy. Point mutations inSMN1 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.

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 3. 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 be 12-13.

Types of SMA

The varying amounts of SMN protein that can be produced from theSMN2 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 Types 1, 2, 3, Adult Onset and SMARD. Type 1, Type 2, Type 3

Rarer forms of SMA

This information sheet focuses on SMA caused by recessive mutations in the SMN1 gene as this is the most common form of SMA and is responsible for SMA Types 1, 2, and 3. Please ask your medical team if you require further information.

Possible future treatments for SMA

SMA results from people having low levels of the SMN protein, we could therefore possibly treat, and maybe even cure, SMA by replacing the SMN protein. Unfortunately, this is not easy. A number of SMN replacement strategies are currently being developed that have great potential for the future treatment of SMA14-15. For more up to date information on current research please see the clinical trials.


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 doctor 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: I have been tested for SMA and the test has come back negative, but my doctor 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 this 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.

Dr James Sleigh – SMA Support UK Research Correspondent
Lesley Luck – SMA Support UK Outreach Worker


Current clinical trials in SMA

Current SMA trials are listed here.


References

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  2. Pennisi, E. (2012) ‘ENCODE project writes eulogy for junk DNA’, Science, 337(6099), pp. 1159-1161.
  3. Lefebvre, S., Bürglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., Benichou, B., Cruaud, C., Millasseau, P., Zeviani, M., Le Paslier, D., Frézal, J., Cohen, D., Weissenbach, J., Munnich, A., and Melki, J. (1995) ‘Identification and characterization of aspinal muscular atrophy-determining gene’, Cell, 80(1), pp. 155-165.
  4. Cusin, V., Clermont, O., Gérard, B., Chantereau, D. and Elion, J. (2003) ‘Prevalence of SMN1 deletion and duplication incarrier and normal populations: implication for genetic counselling’, Journal of Medical Genetics, 40(4), e39.
  5. Sheng-Yuan, Z., Xiong, F., Chen, Y.J., Yan, T.Z., Zeng, J., Li, L., Zhang, Y.N., Chen, W.Q., Bao, X.H., Zhang, C. and Xu, X.M. (2010) ‘Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population’, European Journal of Human Genetics, 18(9), pp. 978-984.
  6. Mostacciuolo, M.L., Danieli, G.A., Trevisan, C., Müller, E. and Angelini, C. (1992) ‘Epidemiology of spinal muscular atrophies in a sample of the Italian population’, Neuroepidemiology, 11(1), pp. 34-38.
  7. Hendrickson, B.C., Donohoe, C., Akmaev, V.R., Sugarman, E.A., Labrousse, P., Boguslavskiy, L., Flynn, K., Rohlfs, E.M., Walker, A., Allitto, B., Sears, C. and Scholl, T. (2009) ‘Differences in SMN1 allele frequencies among ethnic groups within North America’, Journal of Medical Genetics, 46(9), pp. 641-644.
  8. Lunn, M.R. and Wang, C.H. (2008) ‘Spinal muscular atrophy’,The Lancet, 371(9630), pp. 2120-2133.
  9. Sleigh, J.N., Gillingwater, T.H. and Talbot, K. (2011) ‘The contribution of mouse models to understanding thepathogenesis of spinal muscular atrophy’, Disease Models & Mechanisms, 4(4), pp. 457-467.
  10. Burghes, A.H. and Beattie, C.E. (2009) ‘Spinal muscularatrophy: why do low levels of survival motor neuron proteinmake motor neurons sick?’ Nature Reviews Neuroscience, 10, pp. 597-609.
  11. Ruggiu, M., McGovern, V.L., Lotti, F., Saieva, L., Li, D.K., Kariya, S., Monani, U.R., Burghes, A.H. and Pellizzoni, L. (2012) ‘A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy’,Molecular and Cellular Biology, 32(1), pp. 126-138.
  12. McAndrew, P.E., Parsons, D.W., Simard, L.R., Rochette, C., Ray, P.N., Mendell, J.R., Prior, T.W. and Burghes, A.H. (1997) ‘Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number’,The American Journal of Human Genetics, 60(6), pp. 1411-1422.
  13. Mailman, M.D., Heinz, J.W., Papp, A.C., Snyder, P.J., Sedra, M.S., Wirth, B., Burghes, A.H. and Prior, T.W. (2002) ‘Molecular analysis of spinal muscular atrophy and modification of thephenotype by SMN2’, Genetics in Medicine, 4(1), pp. 20-26.
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