The 2021 AGM presentations followed the path established in 2020, with talks scheduled after the AGM on separate days. First up was Professor Henry Houlden of the National Hospital for Neurology and Neurosurgery in London. He talked about the spectrum of HSP genes in the UK and about building a biobank or registry for future biomarkers and trials.
You can watch the presentation here: https://www.youtube.com/watch?v=HtgQO-_vNBQ
What is HSP?
Henry began with an overview of HSP. HSP is a genetic condition caused by a mutation in your genes genes. HSP is usually caused by a mutation in a single gene, and this applies to all people with HSP even if your gene has not yet been identified. It is also important to note that if you have HSP it is unlikely to be the cause of all other issues with your health - HSP may be your main diagnosis, but it will not be the cause of all issues.
Henry showed a few videos of some of the key features of HSP, starting with a spastic gait and toe-walking. He also showed some tremors, some clonus, and later eye issues and balance issues. With a stiff gait it is often difficult to take a step back to steady ones self, which can lead to balance problems.
HSP falls into two main types - 'pure' and 'complex'/'complicated'. 'Pure' HSP has three main symptoms - stiffness, balance issues and pain. 'Complex' HSP has these main symptoms and other symptoms as well, which can include memory/thinking issues, seizures, deafness, speech issues or neuropathy.
HSP onset can be grouped into four categories, those with onset in early childhood, those with onset before age 20, those with onset after age 20, and sporadic/idiopathic HSP. sporadic/idiopathic HSP usually occurs later and often presents a diagnosis challenge.
A typical person with HSP (and no known family history) would start to develop tripping or scuffing issues in their teens or twenties, with comments sometimes made that they are not so good at sport. Over time they would develop some stiffness and some bladder problems or back problems, and ending up getting a diagnosis in their mid thirties.
Prevalence and Inheritance
At the moment the prevalence of HSP in the UK is unknown. Henry suggested that it may be around 1 in 10,000, but this is his view rather than a number backed up by data. A prevalence of 1 in 10,000 would suggest there are 6 to 7 thousand with HSP in the UK (the population being some 66 million).
The two main types of inheritance are dominant and recessive inheritance. For types of HSP which inherit dominantly one parent who has HSP has a 50% chance of passing it onto their children. For types of HSP inherit recessively both parents must carry the HSP gene and pass it on to their child for HSP to occur. People with one copy of the gene are unaffected. In the UK dominant types of HSP are more common than recessive types of HSP, but the prevalence of different types of HSP is not known.
With dominant types Spastin or SPG4 is the most common type. Some 25-45% of people with HSP have the Spastin/SPG4 type of HSP. The next most common dominant types are Atlastin/SPG3A (some 7%) and REEP1/SPG31 (a few percent). Symptoms for SPG3A and SPG31 are similar to those of SPG4.
With recessive types Paraplegin/SPG7 is the most common type, with Spatacsin/SPG11 and SPG15 next. Up until relatively recently it was understood that SPG11 was more common than SPG7 in the UK, however there are now known to be more cases of SPG7. UK biobank data indicates than some 1-2% of the population carries an SPG7 mutation. SPG11 and SPG15 usually are more severe than SPG7.
Over time the number of identified HSP genes is increasing, with Henry expecting that a genetic diagnosis will be possible for all people with HSP in the next 10 years or so.
There are examples of people with dominantly inherited HSP where neither parent has an HSP diagnosis. Historically this has often been due to the affected parent dying an earlier age or because older generations have often avoided getting diagnoses for their health conditions, particularly when then would have had to pay for their appointment.
In the clinic
At the neurogenetics clinic around one third of their patients have HSP, and the proportion has been gradually increasing over time.
The initial step is to get a clinical diagnosis. The person would be examined, their family tree examined, and they would have an MRI or CT scan. The family tree is examined because that can help determine the type of HSP (and the mutation) which affects that family. There would be one gene which affects each family, but the overall number of genes increases which can make it more difficult for doctors and healthcare professionals to keep up to date.
An MRI or CT scan is taken to check that nothing else is going on and that there are no other risk factors to worry about. This is to avoid the situation where an individual is labelled as a person with HSP and all subsequent symptoms are blamed on their HSP. In practice they are just as likely to acquire other illnesses as the rest of the population. If you have not had an MRI/CT scan then you should ask for one next time you see your neurologist.
Those who are affected by speech issues or slurring can be at higher risk of chest infections. Some with SPG7 are affected with vision issues, which can affect their driving as they are moving their head more to look in different directions, with consequential neck ache.
A blood sample is taken for DNA analysis. The DNA is extracted from the blood and is sequenced. The analysis looks for differences between the person and others without HSP of for similarities between the person and family members. Some in the clinic also give a skin fibroblast to aid/promote research.
They like to see people in the clinic every year or two. They have found that face-to-face appointments have been better than telephone appointments.
Treatments
There are no treatments at the moment to reverse HSP, and all treatments are around supporting the person with HSP. Key points are:
- Physiotherapy - to help with spasticity
- Baclofen (or Tizanidine or Dantrolene) - to help with spasticity
- Self-catheterisation or Detrusitol - to help with bladder issues
- Use of high walking sticks - to help with balance/posture
- Gait changes can increase wear and tear on hips/knees
Future Treatments
There are three main paths for developing future drug treatments:
- Repurposing drugs for other conditions. This can be quicker, but as the drugs were not made for HSP they may not work as well as they could.
- Using gene therapy. This approach is being used successfully in Huntingdon's Disease and SMA (Spinal Muscular Atrophy)
- Undertaking basic research into HSP - but this is slower
HSP Registry
One way of making it more enticing for companies to work in HSP is to have a registry of people with HSP who are either ready to take part in trials or who have already donated samples which are ready to be used.
The registry would need to know basic details of the person, including which type of HSP they have. In the UK their data would most likely include their NHS number. The registry would know if there are samples of blood/skin/urine/saliva/spinal fluid available. These samples would ultimately be used as biomarkers to allow the benefits of the candidate drug to be measured.
A registry would also have the potential to help consultants in their diagnosis of HSP in new patients and help the management of HSP in all patients.
It would also be possible for the registry to better inform the overall prevalence of HSP and better estimate the prevalence of each of the types of HSP.
