What is Spinal Muscular Atrophy?

Spinal Muscular Atrophy (SMA) is a rare,

genetically inherited neuromuscular

condition. It causes progressive muscle

weakness and loss of movement due to

muscle wasting (atrophy). This may affect

crawling and walking ability, arm, hand, head

and neck movement, breathing and

swallowing. There are different forms of

SMA and a wide spectrum of how severely

children, young people and adults are

affected.

The most common form of SMA is known as

‘5q SMA’ due to its genetic cause. 5q SMA

includes the different ‘types’ or clinical

classifications – Types 1, 2, 3 and 4.

There are also rarer forms of SMA that

have different genetic (non-5q SMA)

causes. Information about some of

these can be found here:

www.smauk.org.uk/

rarer-forms-of-SMA

www.smasupportuk.org.uk/rarer-forms

Includes

SMA Types 1, 2, 3 & 4 What causes 5q SMA? How is it inherited? How many people are affected? Is there a treatment or cure?

A Guide to:

• SMA Type 1: symptoms usually begin between the ages of 0 and

6 months. It’s the most severe form of SMA and generally, the

➢ SMA Type 1: the most severe form of SMA with symptoms

usually beginning between 0 and 6 months. Generally speaking, the earlier the onset of symptoms, the more severe the condition. Babies are unable to sit without support and may be described as ‘non-sitters’. It‘s not possible to predict life expectancy accurately but for most children, without intervention for breathing difficulties, this has previously been estimated as less than two years3. Evidence suggests that since the International Standards of Care for SMA introduced more proactive managements in 2007, children have been living longer1.

It’s important as you read this guide to remember that:

➢ Each child and adult is affected differently

➢ Although SMA is clinically classified into different ‘Types’ which reflect the severity of its

impact, it is considered a spectrum

➢ For children and adults, the severity of the condition varies from person to person, both

within and between ‘Types’

SMA Types 1, 2, 3 & 4

Symptoms of SMA Types 1, 2 and 3 begin at different ages in childhood. Symptoms of SMA Type 4 begin in adulthood. The Types are defined by the best developmental milestone achieved, for example, if a child is able to walk at some point then they have SMA Type 3.

Sometimes, as well as being diagnosed with a Type of SMA, a child may also be described as ‘strong’ or ‘weak’ or having ‘early onset’ or ‘later onset’. This can be confusing as sometimes this refers to breathing being affected, yet at other times, it may mean age of onset. The international Standards of Care for SMA1,2 talk about classifications a, b and sometimes c – these describe the age of onset of the SMA.

A child / young person’s ability to sit, stand or walk and how their breathing ability is affected by their SMA are also important when it comes to managing the condition. Bearing all of this in mind, broadly speaking, each type of SMA is currently understood to be as follows:

You can read more about SMA Type 1 in ‘Symptoms, diagnosis and effects of 5q SMA’. If you are a parent or carer, you may find it helpful to read our guide, ‘Looking after your child who has had a recent diagnosis of SMA Type 1’.

➢ SMA Type 2: symptoms usually begin between the ages of 7 and 18 months. Children are unable to stand without support and may be described as ‘sitters’. Their weak respiratory muscles can make it difficult for them to cough effectively, which can make them more vulnerable to chest (respiratory) infections. Though this is a serious condition that may shorten life expectancy4, improvements in care standards mean that the majority of people can live long, fulfilling lives.

➢ SMA Type 3a: symptoms usually begin between 18 months and

3 years of age. Children can stand and walk, although this will become more difficult with age and they will need more support over time.

In SMA Type 3b, symptoms usually begin after 3 years. Difficulties with standing and walking usually occur later than they do for children with SMA Type 3a. Depending upon the individual impact of their condition, children and adults with SMA Type 3 may be described as ‘sitters’ or ‘walkers’. Very few people with SMA Type 3 have breathing problems and their life expectancy isn’t usually affected5. Most can live long, fulfilling lives.

➢ SMA Type 4: symptoms begin in adulthood and include mild to

moderate muscle weakness in the arms and legs and some difficulty walking. SMA Type 4 isn’t life-threatening6.

You can read more about SMA Type 4 in ‘Symptoms, diagnosis and effects of 5q SMA’. Our guide, ‘Looking after yourself if you are an adult who has had a recent diagnosis of SMA’ answers many questions asked by adults newly diagnosed with SMA Type 4.

You can read more about SMA Type 2 in ‘Symptoms, diagnosis and effects of 5q SMA’. If you are a parent or carer you may find it helpful to read our guide, ‘Looking after your child who has had a recent diagnosis of SMA Type 2’.

You can read more about SMA Type 3 in ‘Symptoms, diagnosis and effects of 5q SMA’. If you are a parent or carer you may find it helpful to read our guide: ‘Looking after your child who has had a recent diagnosis of SMA Type 3’.

What causes 5q SMA?

➢ The SMN1 gene

All types of 5q SMA affect the nerve cells called lower motor neurons. These are found within the spinal cord and transmit signals to muscles. These nerve cells carry electrical signals from the brain to activate the muscles used for movement such as crawling and walking. These signals control movement of arms, hands, head and neck as well as breathing and swallowing. For these nerve cells to be healthy, our Survival Motor Neuron 1 genes (SMN1 genes7) must produce enough Survival Motor Neuron (SMN) protein. Most people have two copies of the SMN1 gene. People with 5q SMA have two faulty copies of the SMN1 gene, which means they are unable to produce enough SMN protein to have healthy lower motor neurons6. This means these specialist nerve cells in the spinal cord deteriorate. This restricts the delivery of signals from the brain to their muscles, making movement difficult. The muscles then waste due to lack of use - this is known as muscular atrophy. In summary:

Brain sends signals along the spinal cord via nerve cells called lower motor neuron

In SMA, lower motor neurons in the spinal cord deteriorate

Signals cannot efficiently get through to the muscles making movement difficult

Muscles waste (atrophy) due to lack of use

The SMN1 gene is on the fifth chromosome in the region labelled ‘q’. This is why the main types of SMA are often referred to as ‘5q SMA’.

There are other rarer forms of SMA with different genetic causes. For more information on these, please see: www.smauk.org.uk/ rarer-forms-of-sma

➢ The SMN2 gene7

A second gene also has a role in producing SMN protein. This is the Survival Motor Neuron 2 gene (SMN2), sometimes referred to as the SMA “back-up gene”. However, most of the SMN protein produced by SMN2 lacks a key building block that is usually produced by SMN1. This means that while SMN2 can make some functional SMN protein, it cannot fully make up for the faulty SMN1 gene in people with SMA. Unlike most genes, the number of copies of SMN2 on each chromosome can vary from one person to the next8; this can be between 0 – 8 copies. At the population level, the severity of SMA is linked to how much SMN protein is made 1,8,9; there is therefore a general relationship between the number of SMN2 copies (“SMN2 copy number”) and the likely severity of SMA symptoms1,8,9. Having more SMN2 copies is generally associated with less severe SMA symptoms. However, at the individual level, accurate predictions cannot be made about the Type or severity of SMA based on the SMN2 copy number alone1. This is likely to be because other genetic and possibly environmental factors have an influence on the disease. Bearing this in mind, the following table gives a summary of: ➢ how many SMN2 copies the majority of people within each type

of SMA may have (see ‘usual’ column)1 and

➢ the possible range of copy numbers that people within each type of SMA may have (see ‘range’ column)10

SMA Type Usual age of symptoms10 SMN2 copies

‘usual’ number1

‘range’10

Type 1 Younger than 6 months 2 1-3

Type 2 6 – 18 months 3 2-4

Type 3a Under 3 years 3 3-5

Type 3b Over 3 years 4

Type 4 Over 18 years 4-6

Table adapted from Tillmann et al. 201810

How do people inherit 5q SMA? 5q SMA is passed from parents to their children through faulty SMN1 genes. It usually follows an autosomal, recessive pattern of inheritance. This means that:

• People who have inherited two faulty copies of the SMN1 gene (one from each parent) have SMA.

• People who have inherited one faulty copy and one healthy copy of the SMN1 gene (one from each parent) are carriers of SMA. Carriers do not have SMA or any symptoms of SMA.

• People who have inherited two healthy copies of the SMN1 gene (one from each parent) do not have SMA and are not carriers.

When two SMA carriers have a child together, for each pregnancy there is a:

• 1 in 4 (25%) chance that the child will inherit both faulty copies of the SMN1 gene and will have SMA.

• 1 in 2 (50%) chance that the child will inherit one faulty copy and one healthy copy of the SMN1 gene and will be a carrier.

• 1 in 4 (25%) chance that the child will inherit two healthy copies of the SMN1 gene and will not be a carrier or have SMA.

In around 2% of cases of SMA, 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.

For more detailed information, please see our information sheet, ‘The Genetics of 5q SMA’ www.smauk.org.uk/ the-genetics-of-5q-sma

There are other rarer forms of SMA with different genetic causes and different patterns of inheritance. For more information on these, please see: www.smauk.org.uk/ rarer-forms-of-sma

How many people are affected by SMA? Approximately 1 in 40 people carry the faulty SMN1 gene11 - that means there are around 1.6 million carriers in the UK. The incidence is the number of new cases of a condition or disease at any one time. Recent studies indicate that approximately one in every 10,000 babies worldwide are born with a Type of SMA, and that Type 1 SMA accounts for approximately 60% of cases11,12.

In the UK in 2017, there were 755,043 live births13-15. This suggests that in that year approximately 76 babies were born with a type of 5q SMA. The prevalence is how many people are living with a condition or disease in a population at any one time. Recent studies suggest between 1 and 2 people in every 100,000 worldwide have a type of SMA11,12 (which equates to between 10 and 20 people in every million).

In 2017, the UK population was approximately 66 million16. Based on this, it is estimated that between 660 and 1320 people have SMA in the UK at any one time. Previous estimates by clinicians have suggested an upper limit likely to be 2,500. As there is no central information source the exact numbers are unknown.

In 2018, Public Health England (PHE) started to collect data about people diagnosed with SMA in England, through the national congenital anomaly and rare disease register (NCARDRS). In September 2019 they published their first report containing preliminary prevalence data on spinal muscular atrophy type 1. This was based on Hospital Episode Statistics (HES), Office of National Statistics (ONS) mortality data and patient data held by the NCARDRS. In their report they estimate that 1 in 16,320 babies born in England have SMA Type 1 (around 42 babies per year)17.

Is there a treatment or cure for 5q SMA? Although there is currently no cure for SMA, this does not mean that nothing can be done. There are a range of options aimed at managing symptoms, reducing complications of muscle weakness and maintaining the best quality of life. These are outlined in the internationally agreed Standards of Care for SMA 1,2.

➢ Nusinersen / SpinrazaTM

Currently in the UK, the only approved drug treatment for SMA is nusinersen. Essentially, the drug is designed to modify the product of the SMN2 gene to produce more functional 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. For details of who is now able to access nusinersen in the UK, please see www.smauk.org.uk/uk-access-now

➢ Research and further developments There is a considerable amount of research into SMA taking place around the world. This research will not only improve our understanding of the condition, but will also help to develop effective treatments. One area of extensive research is 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.

For the latest developments with drug treatments, the science behind them, and what clinical trials and other research is going on, please go to: www.smauk.org.uk/ treatments-research

To find out more about how nusinersen works and the clinical trial results, please explore this section of our website:

www.smauk.org.uk/ nusinersen

For anyone considering the possibility of nusinersen treatment, it may be helpful to read our information leaflets: www.smauk.org.uk/ treatment-information-leaflets

Resources and support The International Standards of Care for Spinal Muscular Atrophy (2017) can be read / downloaded from here: www.smauk.org.uk/international-standards-of-care-for-sma SMA UK Phone: 01789 267 520 Email: supportservices@smauk.org.uk Website: www.smauk.org.uk

We provide a free Support & Outreach Service for families by email, phone, text and outreach home-visiting. Our experienced team offer personalised support and information and are available to answer questions and talk things through. Though we don’t give medical advice, we can discuss with you the support you and your family can access.

If you're wondering about an aspect of life with SMA, we hope the Living With SMA area of our website will be a helpful starting point, giving you useful information and ideas. It builds on knowledge and advice from the SMA Community and SMA UK's Support Services Team, and covers a whole host of topics, including: health & wellbeing, equipment, homes, education, work, transport, leisure, holidays, financial, and emotional & social support: www.livingwithsma.org.uk

Muscular Dystrophy UK Phone: 0800 652 6352 Website: www.musculardystrophyuk.org MDUK provide information, support, advocacy services and grants towards specialist equipment for people affected by a range of neuromuscular conditions.

Version 1.3 Author: SMA UK Information Production Team Published: September 2018 Last updated: November 2019 Next full review due: September 2021

References

1. Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B,

Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi:10.1016/j.nmd.2017.11.005. Epub 2017 Nov 23. http://smauk.org.uk/international-standards-of-care-for-sma (Accessed 29 August 2018)

2. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone

ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y,Sejersen T; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004. Epub 2017 Nov 23. http://smauk.org.uk/international-standards-of-care-for-sma (Accessed 29 August 2018)

3. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main

M, Crawford TO, Trela A; Participants of the International Conference on SMA Standard of Care (2007) Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 22: 1027-1049. Available at: www.treat-nmd.eu/care/sma/care-standards/ (Accessed: 29 August 2018)

4. Farrar MA, Vucic S, Johnston HM, duSart D, Kiernan MC (2013) Pathophysiological insights

derived by natural history and motor function of spinal muscular atrophy. J Pediatrics 162: 155-159.

5. Zerres K, Rudnik-Schöneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-

Petrusewicz I (1997) A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci 146: 67-72.

6. Lunn MR, Wang CH (2008) ‘Spinal muscular atrophy’, Lancet, 371: 2120-2133.

7. 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, Melki J (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155-165.

8. Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AHM, Prior TW (2002).

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 4: 20–26.

9. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J (1997). Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16: 265–269.

10. R.Tillmann, M. Main, L.Abbot, L. Edel, M. Scoto, F. Muntoni (2018), Spinal Muscular Atrophy

(SMA) type 1, a changing phenotype: implications for motor function and physiotherapy management from the Nusinersen Expanded Access Program (EAP)’ APCP Journal Volume 9 Number 1 (2018)

11. Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller

H (2017) Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy –a literature review. Orphanet J Rare Dis 12: 124.

12. Verhaart IEC, Robertson A, Leary R, McMacken G, König K, Kirschner J, Jones CC, Cook SF,

Lochmüller H. (2017) A multi-source approach to determine SMA incidence and research ready population. J Neruol 264: 1465-1473.

13. Office of National Statistics (2018) ‘Births in England and Wales: 2017’. Available at:

https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthsummarytablesenglandandwales/2017 (Accessed:26 August 2018)

14. National Records of Scotland (2018) Available at:

https://www.nrscotland.gov.uk/news/2018/5000-more-deaths-than-births-in-2017 (Accessed: 26 August 2018)

15. Northern Ireland Statistics and Research Agency (2018) ‘Monthly Births’’. Available at:

https://www.nisra.gov.uk/publications/monthly-births (Accessed:26 August 2018) 16. Office for National Statistics ‘Overview of the UK Population: July 2018.’ Available at:

www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/bulletins/annualmidyearpopulationestimates/mid2017#main-points (accessed 26 August 2018)

17. Public Health England: September 2019 ‘Spinal Muscular Atrophy type 1: National Congenital

Anomaly and Rare Disease Registration Service (NCARDRS) data briefing’ Available at: https://www.gov.uk/government/publications/spinal-muscular-atrophy-type-1-ncardrs-data-briefing/spinal-muscular-atrophy-type-1-ncardrs-data-briefing (Accessed 29 November 2019)

We are grateful to the writers and reviewers who assist us in our information production. A list of who this includes

may be viewed on our website: www.smauk.org.uk/our-writers-and-reviewers-panel or requested from

supportservices@smauk.org.uk

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