It's All In The Genes

RESEARCHERS at St George’s may be close to creating the first treatment to halt the progress of a type of motor neurone disease.

Dr Andrew Crosby and members of the Genetics Group have identified the gene responsible for a form of hereditary spastic paraplegia (HSP), which attacks nerve fibres in the spine and can strike at any age.

In the ‘pure’ form of HSP, patients experience muscle weakness and wasting, gradually losing the use of their legs. Other forms can also affect the brain and eyes.

HSP is part of the wider family of motor neurone degenerative diseases which slowly and relentlessly ravage nerve function. For sufferers — among them Stephen Hawking, who has a related form of the condition — the effects can be devastating.

Despite worldwide research efforts, the underlying cause of HSP has remained elusive — until now. Studies at St George’s have pinpointed mutations in a gene known as CYP7B1 as the most likely basis for the disease.

In the liver, CYP7B1 helps break down cholesterol. In the brain, it provides the main route for the modification of DHEA neurosteroids.

Studies involving family groups found alterations in this gene among people with the ‘pure’ form of HSP, which affects around one in 10,000 in Britain.

‘It’s not common, but it’s a key group,’ said Dr Andrew Crosby, Reader in Medical Genetics, who worked with a team including PhD researcher Maria Tsaousidou.

‘This find is exciting because it provides the first solid proof that defective cholesterol metabolism is associated with motor neuron degenerative disease, and offers a realistic treatment option for these patients.

‘We are now undertaking a range of studies to understand the biology of the mutation, using cell studies and other forms of HSP. The gene impacts on neurosteroid levels, and we are studying these levels to see how important this mechanism is.’

Thirty-eight types of motor neuron disease have been identified, seven of them mapped by scientists at St George’s.

The new research, shortly to be published in the American Journal of Human Genetics, could eventually lead to the development of treatments to halt the progress of HSP in patients who are already showing signs and symptoms, said Dr Crosby.

Individuals in an affected family could even be tested for the defective gene and then treated to prevent onset of the disease, which can occur at any time but is most common in the 20s.

This area of research is the focus of intense interest among scientists across the globe. Dr Crosby stresses that the St George’s work is still at a relatively early stage — and that, for patients who already have HSP, the progress of the disease cannot be reversed.

‘Once you’ve lost a neuron, you are not going to get it back again. But it should be possible to halt progress. What we would hope is we could get a treatment so, whatever loss patients have succumbed to, hopefully it will rest at that point and not get any worse.’

The research team has received ethical approval to carry out biochemical screening tests among volunteers before large-scale trials take place in the spring and summer.