Spinal muscular atrophy types 1 through 4 all result from a single known cause — a deficiency of a protein called SMN, 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 protein 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 similar in structure to SMN1 genes. Most of the protein made from SMN2 genes is short and not functional, but some is full-length and functional. The number of SMN2 genes varies from person to person.
In chromosome 5-related SMA, the more copies of the SMN2 gene that a person has, the more functional SMN protein is available, the later the onset of disease symptoms, and the milder the disease course is likely to be.
When SMA symptoms are present at birth or by the age of 6 months, the disease is called type 1 SMA (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. Typically these babies have two copies of the SMN2 gene, one on each chromosome 5. Over half of all new SMA cases are SMA type 1.
When SMA has its onset between the ages of 7 and 18 months and before the child can stand or walk independently, it is called type 2 or intermediate SMA. Children with type 2 SMA generally have at least three SMN2 genes.
Late-onset SMA (also known as types 3 and 4 SMA, mild SMA, adult-onset SMA and Kugelberg-Welander disease) results in variable levels of weakness.
Type 3 SMA has its onset after 18 months, and children can stand and walk independently, although they may require aids. Type 4 SMA has its onset in adulthood, and people are able to walk during their adult years. People with types 3 or 4 SMA generally have between four and eight SMN2 genes, from which a fair amount of full-length SMN protein can be produced.
For more about the differences among types 1 through 4 SMA, see Signs and Symptoms.
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) is a rare form of SMA caused by defects in the IGHMBP2 gene. Infants with SMARD present with severe respiratory distress as well as muscle weakness.
Another rare form of SMA, distal SMA, more severely affects the hand and feet muscles. Distal SMA can be inherited in a recessive fashion similar to SMA types 1-4, in which both parents contribute a faulty copy of the SMN1 gene. Alternatively, distal SMA can be inherited from just one parent (dominant inheritance). Distal SMA can also be X-linked, meaning the gene defect is on the X chromosome. Like most X-linked diseases, this form of distal SMA is much more likely to occur in males than in females.
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 UBE1 causes X-linked SMA. This form resembles type 1 SMA (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. Like most X-linked diseases, it's much more likely to occur in males than in females.
Flaws in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene on chromosome 14 lead to another rare form of SMA, called SMA-LED. This form affects primarily the muscles in the legs.
While all known forms of SMA are apparently 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 told the diagnosis is SMA but it’s not the chromosome 5-related type, talk with your doctor and perhaps a genetic counselor to find out more about the genetics and prognosis for the particular SMA involved.