Spinal muscular atrophy (SMA) is a type of genetic condition that affects a person’s ability to control the movement of their muscles. This condition is estimated to affect 1 in 6,000 to 10,000 people, and even though everyone with Spinal muscular atrophy has the same gene mutation, the symptoms, onset, and progression of the disease can vary substantially.1
Due to this, Spinal muscular atrophy is usually segmented into four different types. There are also other rare forms of the disease that are caused due to different gene mutations. In order to understand the four types of SMA, it is important to first understand the cause Of Spinal Muscular Atrophy.
What are the Causes of Spinal Muscular Atrophy?
The four types of Spinal Muscular Atrophy are caused due to a deficiency of a protein known as SMN, which refers to ‘survival of motor neuron’. Motor neurons are the nerve cells present in the spinal cord that carry out the responsibility of sending out signals or messages to our muscles.
When there is a mutation or mistake that takes place in both the copies of the SMN1 gene, it can cause a deficiency in the SMN protein. Both copies of the SMN1 gene refers to one copy each on each of the two copies of chromosome 5. If there is little or sometimes absolutely no SMN protein being produced due to the mutation, it can lead to mild to severe problems in motor function.2
The genes that are located next to SMN1, known as the SMN2 genes are also similar in structure to the SMN1 genes. In some cases, they can help offset this SMN protein deficiency that has occurred due to the mutation. However, the number of SMN2 genes tend to vary from person to person. Due to this, the type of Spinal Muscular Atrophy , a person, has also depended on exactly how many SMN2 genes a person has to help make up for the gene mutation in their SMN1 gene. For example, if a person who has chromosome 5-related Spinal Muscular Atrophy has more copies of the SMN2 gene, then they are capable of producing more of the functional SMN protein. In return, they are likely to have milder Spinal Muscular Atrophy along with a later onset of the disease as compared to someone who has lesser copies of the SMN2 gene.3,4
4 Types Of Spinal Muscular Atrophy
Let us look at the various types of Spinal Muscular Atrophy.
1. Type 1 Spinal Muscular Atrophy
Also known as Infantile-onset Spinal Muscular Atrophy or Werdnig-Hoffman Disease, Type 1 Spinal Muscular Atrophy is caused in people who have only two copies of the SMN2 gene, one present one each of the chromosome 5. Over half of all new Spinal Muscular Atrophy diagnoses are usually of type 1 SMA.5
In babies who have type 1 Spinal Muscular Atrophy, you will start observing the symptoms within the first six months after birth. The common symptoms of type 1 Spinal Muscular Atrophy include:
- A weak cry
- Floppy, weak arms and legs, a condition known as hypotonia
- Problems in breathing, swallowing and moving
- An inability to lift up the head or sit without support
In the earlier day, babies born with type 1 Spinal Muscular Atrophy did not usually survive for over two years of age. However, with advancements in treatment and technology, children with type 1 Spinal Muscular Atrophy can continue to live for many years.6
2. Type 2 SMA
Type 2 Spinal Muscular Atrophy is also known as intermediate Spinal Muscular Atrophy, and people with type 2 SMA usually have at least three of the SMN2 genes. The symptoms of this type of SMA tend to become apparent in babies between 7 to 18 months of age.
The symptoms of type 2 Spinal Muscular Atrophy are usually less severe than the symptoms of type 1 SMA and include:
- Weakness in arms and legs
- Tremors in the hands and fingers
- An inability to stand up on their own
- Weak breathing muscles
- Difficulty coughing
- Presence of scoliosis, or a curved spinal cord
Type 2 Spinal Muscular Atrophy has a somewhat outlook than type 1 Spinal Muscular Atrophy. People with type 2 SMA may still have a shorter life expectancy, but most people with this condition go on to live well into their adulthood, living long lives. People with type 2 Spinal Muscular Atrophy usually will need to use a wheelchair to get around, and they may also need some other equipment that can help them breathe better during the night.7,8
3. Type 3 SMA
Type 3 SMA is also known as mild Spinal Muscular Atrophy, late-onset SMA, and Kugelberg-Welander disease. The symptoms type 3 SMA is known to be variable. People with this type of SMA tend to have between four to eight SMN2 genes.
The symptoms of type 3 Spinal Muscular Atrophy start before a child turns 18 months of age. The disease is typically diagnosed by the time the child turns three years, but the exact age of onset can vary from person to person. In fact, many people with type 3 SMA may not experience any symptoms until they reach early adulthood.
The symptoms of type 3 Spinal Muscular Atrophy also vary from person to person. Most people with this condition are able to usually stand and walk by themselves, but over time, they may lose their ability to walk as they get older. Some of the other symptoms of type 3 Spinal Muscular Atrophy include:9
- Scoliosis
- Balance problems
- Difficulty getting up from a seated position.
- Difficulty going up the stairs
- Difficulty running
Type 3 Spinal Muscular Atrophy does not tend to make any change in a person’s life expectancy, but some of them are at a risk of becoming overweight. The bones of affected people may also become weak and brittle, breaking easily.10
4. Type 4 SMA
Type 4 Spinal Muscular Atrophy is also known as adult-onset Spinal Muscular Atrophy. People with this type of Spinal Muscular Atrophy have been found to have between four to eight SMN2 genes. This allows the body to produce a sufficient amount of the normal SMN protein, due to which the symptoms of Spinal Muscular Atrophy are usually delayed till early adulthood. Type 4 Spinal Muscular Atrophy is the least common type of Spinal Muscular Atrophy out of these four types.
Symptoms of type 4 Spinal Muscular Atrophy tend to begin during early adulthood, usually after the age of 35. Type 4 SMA tends to worsen over time, and symptoms may include:
- Difficulty walking
- Twitching and/or shaking muscles
- Weakness in the feet and hands
Type 4 Spinal Muscular Atrophy has no effect on a person’s life expectancy. The quality of life is also not much affected since the muscles used for swallowing, and breathing is not usually affected.11
Other Types of SMA
While these four types of Spinal Muscular Atrophy are more commonly diagnosed, there are some other types of Spinal Muscular Atrophy that are rare and are caused by various gene mutations, other than the ones that affect the SMN protein. These are forms of Spinal Muscular Atrophy include:
- Distal SMA: This rare form of Spinal Muscular Atrophy is caused by gene mutations in several genes, including the GARS, UBA1, and DYNC1H1. The disease affects the nerve cells in the spinal cord, and symptoms tend to begin during adolescence. The symptoms of distal SMA include weakness or cramps and wasting away of the muscles. Distal SMA does not have any effect on a person’s life expectancy.12
Spinal Muscular Atrophy with Respiratory Distress (SMARD): This is a very rare type of Spinal Muscular Atrophy that is caused by a mutation of the gene known as IGHMBP2. This disease is diagnosed in infants, and it can cause severe breathing and swallowing problems.13
Spinal-Bulbar Muscular Atrophy (SBMA) or Kennedy’s Disease: This is another rare type of Spinal Muscular Atrophy that has been found to affect mostly males. It tends to begin between the ages of 20 and 40 years, and symptoms may include muscle cramps, tremors of the hands and fingers, weakness of the limbs, and twitching. While this disease can also lead to difficulty n walking later on in life, but this type of Spinal Muscular Atrophy usually does not change a person’s life expectancy.14,15
Conclusion
There are majorly four types of chromosome 5-related spinal muscular atrophy, and they are roughly related to the age at which a person first experiences the symptoms. The type of Spinal Muscular Atrophy also depends on the number of the SMN2 genes a person has that helps balance the mutation in the SMN1 gene. Generally, the earlier is the age of onset, the lesser are the copies of SMN2, and therefore, a greater impact is there on motor function.
Children with type 1 Spinal Muscular Atrophy tend to have the lowest level of functioning. Type 2, 3, and 4 SMA causes less severe symptoms, and at the same time, it is important to understand that Spinal Muscular Atrophy does not have any impact on a person’s brain or on their ability to learn.
The other rare forms of Spinal Muscular Atrophy, like distal SMA, SBMA, and SMARD are all caused by different gene mutations and not the chromosome 5-related mutations. They also have a completely different pattern of being passed on to a child. If you or anyone in your family has Spinal Muscular Atrophy, it is a good idea to talk to your doctor to find out more about the genetic link of SMA and the outlook for the different types of Spinal Muscular Atrophy. There are many support groups and online forums as well dedicated to the different types of Spinal Muscular Atrophy and interacting with others who have the same condition can help you learn more about how to cope with this disease.
- Conditions, G., 2020. Spinal Muscular Atrophy: Medlineplus Genetics. [online] Ghr.nlm.nih.gov. Available at: <https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy#statistics> [Accessed 2 December 2020].
- Li, W., 2017. How do SMA-linked mutations of SMN1 lead to structural/functional deficiency of the SMA protein?. PloS one, 12(6), p.e0178519.
- Monani, U.R., Lorson, C.L., Parsons, D.W., Prior, T.W., Androphy, E.J., Burghes, A.H. and McPherson, J.D., 1999. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Human molecular genetics, 8(7), pp.1177-1183.
- Ruhno, C., McGovern, V.L., Avenarius, M.R., Snyder, P.J., Prior, T.W., Nery, F.C., Muhtaseb, A., Roggenbuck, J.S., Kissel, J.T., Sansone, V.A. and Siranosian, J.J., 2019. Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Human genetics, 138(3), pp.241-256.
- Muscular Dystrophy Association. 2020. Diseases – SMA – Types Of Overview | Muscular Dystrophy Association. [online] Available at: <https://www.mda.org/disease/spinal-muscular-atrophy/types> [Accessed 6 December 2020].
- Baranello, G., Servais, L., Day, J.W., Deconinck, N., Mercuri, E., Klein, A., Darras, B., Masson, R., Kletzl, H., Cleary, Y. and El-Khairi, M., 2019. FIREFISH Part 1: 1-Year Results on Motor Function in Babies with Type 1 SMA (S25. 003).
- Mercuri, E., Baranello, G., Kirschner, J., Servais, L., Goemans, N., Pera, M.C., Buchbjerg, J., Yeung, W.Y., Kletzl, H., Gerber, M. and Czech, C., 2019. Update from SUNFISH part 1: safety, tolerability and PK/PD from the dose-finding study, including exploratory efficacy data in patients with Type 2 or 3 spinal muscular atrophy (SMA) treated with risdiplam (RG7916)(S25. 007).
- Testa, M.B.C., Pavone, M., Bertini, E., Petrone, A., Pagani, M. and Cutrera, R., 2005. Sleep-disordered breathing in spinal muscular atrophy types 1 and 2. American journal of physical medicine & rehabilitation, 84(9), pp.666-670.
- Chabanon, A., Seferian, A.M., Daron, A., Péréon, Y., Cances, C., Vuillerot, C., De Waele, L., Cuisset, J.M., Laugel, V., Schara, U. and Gidaro, T., 2018. Prospective and longitudinal natural history study of patients with type 2 and 3 spinal muscular atrophy: baseline data NatHis-SMA study. PLoS One, 13(7), p.e0201004.
- Walter, M.C., Wenninger, S., Thiele, S., Stauber, J., Hiebeler, M., Greckl, E., Stahl, K., Pechmann, A., Lochmüller, H., Kirschner, J. and Schoser, B., 2019. Safety and treatment effects of nusinersen in longstanding adult 5q-SMA type 3–a prospective observational study. Journal of neuromuscular diseases, 6(4), pp.453-465.
- Souza, P.V.S., Pinto, W.B.V.D.R., Ricarte, A., Badia, B.D.M.L., Seneor, D.D., Teixeira, D.T., Caetano, L., Gonçalves, E.A., Chieia, M.A.T., Farias, I.B. and Bertini, E., 2020. Clinical and radiological profile of patients with spinal muscular atrophy type 4. European Journal of Neurology.
- Harding, A.E. and Thomas, P., 1980. Hereditary distal spinal muscular atrophy: a report on 34 cases and a review of the literature. Journal of the neurological sciences, 45(2-3), pp.337-348.
- Goemans, N.M.L.A., Matthijs, G., Hubner, C., Grohmann, K., Varon, R., Sciot, R., Naulaers, G. and van Hole, C., 2002. Spinal muscular atrophy with respiratory distress (SMARDI) clinico-pathological aspects of 3 new cases. Neuromuscular Disorders, 12(7-8), p.736.
- Chahin, N., Klein, C., Mandrekar, J. and Sorenson, E., 2008. Natural history of spinal-bulbar muscular atrophy. Neurology, 70(21), pp.1967-1971.
- Fratta, P., Nirmalananthan, N., Masset, L., Skorupinska, I., Collins, T., Cortese, A., Pemble, S., Malaspina, A., Fisher, E.M., Greensmith, L. and Hanna, M.G., 2014. Correlation of clinical and molecular features in spinal bulbar muscular atrophy. Neurology, 82(23), pp.2077-2084.
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