Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Spinal muscular atrophy (SMA) is a group of genetic diseases characterized by muscle weakness and wasting. SMA affects mostly infants and children, and is the most common genetic causes of childhood fatality.1
The disease is caused by lower than normal levels of a protein called survival motor neuron (SMN).2 This protein is essential for the survival of nerve cells that control muscle movement. When the body cannot produce enough SMN protein, motor neurons die. This impairs the signals they normally send to voluntary muscles to control their movement. Without nerve signals coming from motor neurons, muscle cells also die. This leads to muscle weakness and atrophy.
Spinal muscular atrophy classification is based on the severity of the disease. There are 5 SMA types in total, with type 0 being the most severe and type 4 the least severe.3
Two genes encode SMN protein: SMN1 and SMN2, both located on chromosome 5.2 In patients with SMA, there is a mutation in the SMN1 gene, which means that the only SMN protein that is available in the body comes from the SMN2 gene. However, most of the SMN protein from this gene is nonfunctional and quickly degraded by cells. The number of SMN2 genes varies from person to person and impacts SMA classification. In SMA, the more copies of the SMN2 gene there are, the less severe the disease is, as this increases the amount of functional SMN protein that cells can make.
SMA Type 0
SMA type 0 is the prenatal form of the disease and the most severe, characterized by reduced fetal movement observed at 30 and 36 weeks of gestation.14 After birth, infants present with joint abnormalities and severe muscle weakness. They also experience difficulty swallowing and respiratory failure4. Infants born with SMA type 0 usually live for fewer than 6 months.
Read more about SMA type 0.
SMA Type 1
SMA type 1, also called Werdnig-Hoffmann disease, is the most common type of SMA with 50% to 70% of patients being affected by this type of disease. These patients usually have 2 to 3 copies of the SMN2 gene.7
Symptoms of the disease usually appear within 6 months of birth. They include generalized muscle weakness, a weak cry, and breathing difficulty.5 Like patients with SMA type 0, those with SMA type 1 have difficulty swallowing and sucking. Babies with SMA type 1 can never sit unaided. They usually die before age 2 due to respiratory failure, though there is a variance in life span depending on the degree of respiratory function as well as therapeutic intervention.8
Read more about SMA type 1.
SMA Type 2
Symptoms of SMA type 2, also called Dubowitz disease, usually appear between 6 and 12 months of age.8 Muscle weakness affects the legs more than the arms. Affected babies can sit independently but usually lose this ability by their mid-teens. They are never able to walk independently, and they often experience respiratory infections. Patients with SMA type 2 can live into adulthood with adequate treatment. These patients typically have 3 copies of the SMN2 gene.7
Read more about SMA type 2.
SMA Type 3
In SMA type 3 or Kugelberg–Welander disease, symptoms can appear any time from 18 months of age to early adulthood.1 This type of disease is seen in about 30% of all SMA patients.9 Affected individuals can stand and walk but experience frequent falls. They may also find it difficult to get up from a seated position and climb stairs. As the disease progresses, they may lose the ability to stand and walk and may need to use a wheelchair.5 Frequent respiratory infections are also common. Life expectancy is close to normal. These patients usually have 3 to 4 copies of the SMN2 gene.7
Read more about SMA type 3.
SMA Type 4
This is the least severe form of SMA and only affects adults. SMA type 4 accounts for less than 5% of all SMA cases.9 Patients have 4 to 8 copies of the SMN2 gene.7
Symptoms usually appear after age 30. As the disease progresses, patients may start to experience progressive muscle weakness, especially in their legs. Patients with SMA type 4 retain the ability to stand and walk, and life expectancy is the same as for someone without the disease.5
Read more about SMA type 4.
Other SMA Classification Types
There are also other SMA types that are not caused by mutations in the SMN1 gene and not linked to chromosome 5. Other SMA classifications include SMA with respiratory distress (SMARD), distal SMA, and X-linked SMA.5 These types of SMA greatly vary in severity and in terms of muscles that they affect.
SMARD specifically affects the lower motor neurons and is characterized by severe respiratory distress in addition to muscle weakness.10 It is caused by mutations in the IGHMBP2 gene, which is involved in DNA transcription and translation.11
Distal SMA mostly affects the distal muscles12 and can be caused by mutations in a number of genes including UBA1, DYNC1H1, TRPV4, PLEKHG5, GARS, and FBXO38.
X-linked SMA resembles SMA type 1 in that it affects infants and young children. Symptoms are severe and include low muscle tone and congenital contracture. It is caused by a mutation in the UBA1 gene, which resides on the X-chromosome. As such, the disease mainly affects males.
Reviewed by Michael Sapko, MD on 7/1/2021
- Spinal muscular atrophy. National Center for Biotechnology Information. Accessed May 30, 2021.
- Spinal muscular atrophy. Medline Plus. Accessed May 30, 2021.
- Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33(4):831-846. doi:10.1016/j.ncl.2015.07.004
- Grotto S, Cuisset JM, Marret S, et al. Type 0 spinal muscular atrophy: further delineation of prenatal and postnatal features in 16 patients. J Neuromuscul Dis. 2016;29;3(4):487-495. doi: 10.3233/JND-160177
- Types of SMA. Muscular Dystrophy Association. Accessed May 30, 2021.
- Type 1. SMA Europe. Accessed May 30, 2021.
- Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7.doi:10.3389/fmolb.2016.00007
- Spinal muscular atrophy. National Organization for Rare Disorders. Accessed June 2, 2021.
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. doi:10.1002/mus.24497
- Spinal muscular atrophy with respiratory distress (SMARD). Spinal Muscular Atrophy UK. Accessed June 2, 2021.
- IGHMBP2 gene. Medline Plus. Accessed May 30, 2021.
- Spinal muscular atrophy, distal, autosomal recessive, 3; DSMA3. Online Mendelian Inheritance in Man. Accessed May 30, 2021.
- Kennedy’s disease information page. National Institute of Neurological Disorders and Stroke. Accessed May 30, 2021.
- Prior TW, Leach ME, Finanger E. Spinal muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington; 2000. Updated December 3, 2020. Accessed May 30, 2021.