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 genes) 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 neurons. 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.
The SMN2 gene
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 next; this can be between 0 – 8 copies. At the population level, the severity of SMA is linked to how much SMN protein is made; there is therefore a general relationship between the number of SMN2 copies (“SMN2 copy number”) and the likely severity of SMA symptoms. 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 alone. This is likely to be because other genetic and possibly environmental factors have an influence on the disease.
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 usually 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.