Spinal Muscular Atrophy (SMA)
Types of SMA
SMA linked to chromosome 5
Spinal muscular atrophy (SMA) types 1 through 4 all result from a single known cause — a deficiency of a protein called SMN, which stands for "survival of motor neuron."
Deficiency of SMN protein occurs when a mutation (flaw) is present in both copies of the SMN1 gene — one on each chromosome 5. Normally, most of the proteins made from SMN1 genes is full-length and functional, but when mutations occur, little or no full-length, functional SMN protein is produced.
This loss can be partially offset by the presence of neighboring SMN2 genes, which are 99% similar to SMN1 genes. The number of SMN2 gene copies varies from person to person. Most of the proteins made from SMN2 genes are short and not functional, but some are full-length and functional.
In chromosome 5-related SMA, the greater the number of SMN2 gene copies a person has, the more functional SMN protein is available, and thus, the later the onset of disease symptoms and the milder the disease course.
SMA type 0 is characterized by a decrease in fetal movement during pregnancy. At birth, patients with SMA type 0 present with severe weakness and hypotonia. Often, these patients present with lack of reaction to stimuli, facial diplegia (facial paralysis), and congenital heart defects.1,2,3 Patients born with type 0 SMA die by the age of 6 months and sometimes as early as 1 month.
When SMA symptoms are present at birth or by the age of 6 months, the disease is called SMA type 1 (also called infantile onset or Werdnig-Hoffmann disease). Babies typically have generalized muscle weakness, a weak cry, and breathing distress. They often have difficulty swallowing and sucking and don't reach the developmental milestone of being able to sit up unassisted. These babies have increased risk of aspiration and failure to thrive. Typically, these babies have two or three copies of the SMN2 gene.4
When SMA has its onset between the ages of 3 and 15 months and before the child can stand or walk independently, it is called SMA type 2, or intermediate SMA or Dubowitz disease. Children with SMA type 2 generally have three copies of the SMN2 gene.5 Muscle weakness is predominantly proximal (close to the center of the body) and involves the lower limbs more than the upper limbs. Usually, the face and the eye muscles are unaffected.4
Late-onset SMA (also known as SMA types 3 and 4, mild SMA, adult-onset SMA and Kugelberg-Welander disease) results in variable levels of weakness. Patients with type 3 SMA have 3 to 4 copies of the SMN2 gene. SMA type 3 (juvenile onset) accounts for 30% of overall SMA cases.5 Symptoms usually appear between age 18 months and adulthood. Affected individuals achieve independent mobility. However, proximal weakness in these patients might cause falls and difficulty with climbing stairs. Over time, many lose their ability to stand and walk so instead use a wheelchair to move around. Most of these patients develop foot deformities, scoliosis, and respiratory muscle weakness.
SMA type 4 is late-onset and accounts for less than 5% of overall SMA cases.5 These patients have four to eight copies of the SMN2 gene.4 Age of onset is not defined but is usually after age 30. Type 4 is a mild form of SMA and therefore lifespan remains normal. Patients are able to achieve motor milestones and maintain their mobility throughout life.
For more about the differences among SMA types 1 through 4, see Signs and Symptoms.
SMA not linked to chromosome 5
Other forms of SMA are not related to a deficiency of SMN protein, arising instead from defects in different genes on different chromosomes. These forms vary greatly in severity and in the muscles most affected.
Spinal muscular atrophy with respiratory distress (SMARD), also known as autosomal recessive distal spinal muscular atrophy (DSMA1), is a rare form of SMA caused by defects in the IGHMBP2 gene. Infants with SMARD have severe respiratory distress as well as muscle weakness; there tends to be a high frequency of intrauterine growth restriction and premature birth.
A number of genetic causes have been identified for distal SMA, which is associated with varying symptoms and severity. Some of the genes shown to cause various forms of distal SMA include UBA1, DYNC1H1, TRPV4, PLEKHG5, GARS, and FBXO38. Some of these forms of SMA overlap with another disease called Charcot-Marie-Tooth disease (CMT). Diagnosis typically depends on the degree of motor versus sensory symptoms observed in the patient.
A mutation in an X-chromosome gene called UBA1 causes X-linked SMA (XL-SMA or SMAX2). This form resembles SMA type 1 (see above) in its very early age of onset and severity of symptoms. Joints as well as muscles may be affected in X-linked SMA. This rare disorder is characterized by hypotonia (low muscle tone), lack of reaction to stimuli, and congenital contractures. Like most X-linked diseases, it's much more likely to occur in males than in females.
While all known forms of SMA are genetic, they result from defects in different genes and have different inheritance patterns and implications for family planning.
If you or your child has been diagnosed with non-chromosome 5-related SMA, talk with your doctor and a genetic counselor to find out more about the genetics and prognosis for the particular type of SMA involved.
- Rudnik-Schöneborn, S. et al. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J. Med. Genet. (2008). doi:10.1136/jmg.2008.057950
- Grotto, S. et al. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients. J. Neuromuscul. Dis. (2016). doi:10.3233/JND-160177
- Menke, L. A. et al. Congenital heart defects in spinal muscular atrophy type I: A clinical report of two siblings and a review of the literature. Am. J. Med. Genet. Part A (2008). doi:10.1002/ajmg.a.32233
- Butchbach, M. E. R. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Front. Mol. Biosci. (2016). doi:10.3389/fmolb.2016.00007
- Arnold, W. D., Kassar, D. & Kissel, J. T. Spinal muscular atrophy: Diagnosis and management in a new therapeutic era. Muscle and Nerve (2015). doi:10.1002/mus.24497