2020 AGM - Insights from a large regional HSP cohort - Dr Channa Hewamadduma

For the 2020 AGM the technical presentations were held digitally via the Zoom platform, and each one was held on a different day. This blog post covers the second, Insights from a large regional HSP cohort, presented by Dr Channa Hewamadduma from Royal Hallamshire Hospital in Sheffield.

HSP

Channa began with a brief introduction to HSP, acknowledging that it is very variable between patients. He described that the SPG genes are numbered in the order of their discovery, and it took a long time to identify the gene for SPG3 and as a consequence this is called At-Last-In or Atlastin!

The spasticity in HSP is due to the degeneration of the motor axons in the spinal cord. He described that, as a parallel, if the diameter of the motor axon were the diameter of a football, then the length of the axon would be 7 football stadia!

Understanding the potential effects of HSP on an individual requires knowing about which type of HSP the person has. In a cohort of HSP patients some will have a family history, but many will not, they are the first person to be affected. The Sheffield cohort has 420 patients, with a clinical dataset for 371 and a gene identified in 211. Of those with a gene identified about 60% are Spast/SPG4 and around a quarter are Paraplegin/SPG7. SPG7 was thought to be rare, but may not be. SPG7 has a later onset. Cerebral palsy has been a common misdiagnosis for younger HSP patients.

Inheritance and Optic Atrophy 

More than 40% of patients have bladder involvement and around 40% have pain or spasms. More than half of people with complex HSP have optic atrophy. With optic atrophy problems are spotted when the vision is challenged.

SPG7 is one of the genes which shows the spectra of the different overlaps with other conditions and effects. 10% of those in the Sheffield ataxia clinic have SPG7. SPG7 was discovered in 1998. Sheffield has 55 SPG7 patients, and there is a spread between those with HSP, those with ataxia and those with both. The mean age of onset is 42 years.

Further detail was given on optic atrophy. If people are less able to move their eyes they may have been told they have had a stroke rather than have HSP. Optic atrophy in HSP may mean that people are not able to move their eyes equally in every direction. They are hoping to be able to use this as a biomarker for HSP. 

An analysis of published data shows that the age of onset of HSP varies with where the mutation occurs within the gene. If the patient has inherited the same mutation from both parents then their onset may be later than if the patient has inherited different mutations from each parent. If the mutation is sufficient to prevent the protein from working (loss of funciton), the patient would have greater spasticity.

The Sheffield Clinic 

Channa described the in-clinic process for patients, getting an assessment of spasticity, coordination, visual, mood, gait and more. They have a range of interventions available. They are planning to identify the potential for a gait biomarker, to look at the natural progression of HSP and look at the differences between types of HSP.

They have been experimenting with a single sensor gait monitoring, worn on the lower back, which can be used to see how the gait has been affected. Some data was presented looking at a 10m walk test, where a person stands, walks 10m, turns, returns and then sits. Those with SPG4 tend to have more problems standing up, whereas those with SPG7 have more problems sitting down. The gait analysis can also spot effects in mildly affected, which gives them a "trial ready" group of patients.

Future Plans

They are hoping to be able to analyse differences in neuro-imaging to help predict how HSP could progress in an individual.

They are also working on a drug screening programme, looking at the effects of different drugs on cells, from SPG7 , using drugs identified through re-purposing programmes. A high content imaging screen is used to differentiate between cells and controls.

You can watch the whole presentation on YouTube: https://www.youtube.com/watch?v=s3qZqLnNpBY 

Q&A

In the Q&A there were a few interesting points. 

There is no difference between the terms paraplegia and paraperisis.

There are differences in the mutations in specific types of HSP around the world.

Some people get benefits from co-enzyme Q10, some from CBD oils and some from gluten free diets. A study is planned around the gluten free diet.

For each type of HSP there can be many different mutations. Some of the mutations are more common than others, and there is some variation in the mutation type/location in particular parts of the world. 

  

2020 AGM - A Eureka Moment - Prof Andrew Crosby Dr Emma Baple

For the 2020 AGM the technical presentations were held digitally via the Zoom platform, and each one was held on a different day. This blog post covers the first, A Eureka Moment, presented by Professor Andrew Crosby and Dr Emma Baple from Exeter University. They presented together, alternating between sections of the presentation. 

Andrew began by explaining that his interest in HSP stems from his belief that its later onset and slower progression make it the kind of condition where it is possible to slow or prevent progression.

HSP

Emma gave an overview of HSP, noting that the differences between the types of HSP is very large. The common feature is progressive lower limb stiffness and weakness, but beyond that it is difficult to draw conclusions about how a person is affected. HSP is a condition which affects the upper motor neurons, which sit in the spine and provide the connection between the brain and the lower motor neurons which then connect to muscles. The symptoms of HSP are progressive because of the gradual deterioration of the upper motor neurons over time.

Over 80 different genes have been identified for HSP. Overall we have some 22,000 genes in our DNA, each making a protein which is responsible for the development or function of an aspect of us. A spelling mistake in a gene can cause it not to function, and HSP is often associated with spelling mistakes in the genes which are part of the operation of the upper motor neurons. 

The team at Exeter have been responsible for identifying 15 different HSP genes to date. They are also looking into commonalities between types of HSP.

When they see someone in clinic with HSP that person often wants to know if they will develop HSP or not. Particularly people want to know when they will develop symptoms, how HSP and symptoms will develop over time, and what will the effect of HSP be on their lives. A genetic test can answer if someone will get HSP, but it is only the first step.

Fat Processing

The function of most of the genes which are affected in HSP are not know. However, the function of the gene which is responsible for SPG5 is well known. SPG5 was discovered by the Exeter team. The function of the gene is known to process fats within a cell in a specific particular way. From this, we can be sure that this fat processing pathway is important in the way that upper motor neurons work, and that disruptions in the pathway can cause HSP.

The next step was then to see if the other HSP genes were also involved with the same or similar fat processing pathways. It was found that many of the other HSP genes are responsible for the same or similar pathways as SPG5, and this hypothesis has been published in Brain: https://academic.oup.com/brain/article/143/4/1073/5679762 

Additionally, there are similarities and overlaps with HSP and other degenerative motor neuron conditions - which means that if a treatment can be developed for HSP it may also benefit those with other similar conditions.

Various work is being undertaken which is showing that the hypothesis is most likely correct. The work has involved cellular models and new methods to analyse fat processing pathways so that the effects of each HSP gene in the fat processing pathway can be investigated.

Future Plans

Their future plans are to allow a completely different approach to testing. At the moment tests are looking for the specific known HSP genes, whereas the new understanding allows the test to look at the fat processing pathways instead, which avoids the uncertainties with interpreting genetic test results. They are hoping to be able to do this from a standard 10ml blood sample. 

The approach to potential treatments also varies. The aim is to look for treatments which have potential to alter the affected fat processing pathway. Any that are found can be tested in a clinical trial. The crux of these two things is that they would expect to see an improvement in the fat processing pathway with a treatment, and that improvement should be detectable from the blood test. The detection of the improvement from the blood test should be more certain than seeing a change in how HSP afffects a person with their day-to-day symptom variation. Essentially the fat processing pathway is a biomarker for HSP.

Q&A

From the Q&A at the end there were some interesting questions.

A question was asked around gene editing - this is a lab-based technique for editing one cell. These techniques cannot be used in the bodies, so it is a tool for studying rather than a tool for altering someones DNA in the body. 

Although this presentation talks about fat processing, this is not the same as the levels of fat in your diet. The management of fat/cholesterol in the blood is not the same as the processing of fats/cholesterols in the cells. There is no evidence which links levels of fat/cholesterol's in the body with HSP, although there are several with HSP who also have issues with digestion. This is an area where further investigation is needed.