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Genetics

SMA is a genetic neuromuscular disease that is passed down through families.Genetic conditions are caused by differences or ‘faults’ in our genes.

Genes involved in SMA:

The SMN1 gene: SMA is caused by a mutation(an unusual change or ‘fault’ in the genes is known as a mutation) in the Survival Motor Neuron Gene 1 (SMN1). In a healthy person, two copies of the SMN1 gene are present and it produces a protein—called survival motor neuron protein or SMN protein—that is critical to the function of the nerves that control our muscles. Without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness.

People with SMA have two faulty copies of the SMN1 gene. This means they are unable to produce enough SMN protein to have healthy lower motor neurons.

The SMN2 gene: A second gene also has a role in producing SMN protein. This is the Survival Motor Neuron 2 (SMN2) gene, sometimes referred to as the SMA “back-up gene”.

SMN2 has an important single base (nucleotide) difference from SMN1. This causes a small chunk of the gene, called Exon 7, to be excluded in the majority of SMN protein that the SMN2 gene makes. It is estimated that only about 10% of the SMN protein made from SMN2 is functional.

Figure adapted from Burghes, A.H. and Beattie, C.E.

 

 

Unlike most genes, the number of copies of SMN2 on each chromosome can vary from one person to the next.

As the severity of a person’s SMA has been linked to how much SMN protein a person makes, there is therefore a broad relationship between the number of SMN2 copies a person has (“SMN2 copy number”) and the likely severity of their symptoms. Having more SMN2 copies is generally associated with less severe SMA symptoms. However, 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 factors also have a modifying influence.

Inheritance of these Genes

People have 23 pairs of chromosomes. SMA is an autosomal recessive condition. SMA, the Survival Motor Neuron 1 (SMN1) gene is located on the fifth autosomal chromosome, in the region labelled ‘q’. Almost all patients (>95%) with the most common forms of SMA have deletions of SMN1 exon 7; the loss of exon 7 abolishes production of SMN1 protein.

Autosomal conditions affect both males and females equally.

In an autosomal recessive condition like SMA:

a person will only have SMA if they inherit two faulty copies of the SMN1 gene.

A person who carries one faulty copy of the gene and one healthy copy will not have the condition but is a carrier. They do not have any symptoms, but the faulty gene can be passed on to their children.

How will this affect the children?

The chances of the children being carriers or having SMA will depend on whether you or your partner have SMA or are carriers. The chances stay the same for each pregnancy; having one child who has SMA or is a carrier doesn’t change the chances for any further children. Each copy of the gene (healthy or faulty) has the same chance of being passed on. This happens randomly, like the result of a coin toss.

The following diagrams show what the chances are in different families.

For the purpose of the diagrams, a ‘non-carrier’ means a person who does not carry the faulty gene and does not have SMA.

Autosomal recessive family 1: Both parents are carriers

For each pregnancy, the chances are:

  • Child will not have SMA and won’t be a carrier: 1 in 4 chance (25%)
  • Child will not have SMA but will be a carrier: 2 in 4 chance (50%)
  • Child will have SMA: 1 in 4 chance (25%)

Autosomal recessive family 2: One parent is a carrier the other is a non-carrier

For each pregnancy, the chances are:

  • Child will have SMA: not possible
  • Child will not have SMA and won’t be a carrier: 2 in 4 chance (50%)
  • Child will not have SMA but will be a carrier: 2 in 4 chance (50%)