AGM2015: Insights into HSP from Drosophila - Dr Cahir O'Kane

Dr Cahir O'Kane works at the Department of Genetics at the University of Cambridge.

Dr O'Kane's talk was around the study of HSP in Drosophila - also known as fruit flies. The first aspect was why do we do this. Firstly, they have a short development period, going from egg to adult in around 10 days. Also they are small, so one wall of the room at Cambridge can hold 15,000 flies. They have 4 of these rooms and there are several groups working with these flies.

Flies and humans had a common ancestor with humans around 600 million years ago, which means that flies share about 80% of their genes with us, including the HSP genes. The team are able to breed paraplegic larvae, and as they age they lose the ability to climb. You can see this here: http://labs.cellbio.duke.edu/kinesin/WTKHClarvae.html.

These flies have axons in a similar way to humans. Nerve fibres or axons are typically up to 10,000 times longer than a cell body, and cell engineering is needed to maintain the axons. In HSP the longer axons breakdown first.

We have around 20,000 genes and the fly has around 14,000. Over 70 HSP genes have been cloned, and more continue to be found, around one every couple of months. Each gene disrupts a particular protein. Figure 2 here http://sp-foundation.org/file_download/510e252f-c9ec-484c-a90b-8f95372a499f shows which HSP genes affect which parts of the nerve fibre. Within this figure tubular endoplasmic reticulum (ER) can be seen, which forms a network within the cell.  The axons in the fly have a similar ER shape.

Some of the HSP proteins have roles in the integrity of axonal ER in any organism. The research on the flies shows that if a fly is bred with the removal of one of the SPG/HSP genes there are mild effects, and with the removal of multiple HSP genes the ER becomes fragmented - and the nerve no longer functions as intended.

What does the future hold? It is possible that the functions of axonal ER could be altered by drugs, however at the moment it is not known which of these are important to maintain the axon.

The researchers have shown that it is possible to genetically reverse HSP in flies, but they are some way off being able to do this in humans in the embryo. The two of the issues putting this into practve are that there is a much larger risk of miscarriage, and that this is prevented by biomedical regulations (ethics). The researchers dont know all about neurons yet - if the letters in the DNA were printed in a book the human genome would take around 2000 books to print it all. Each gene within the DNA is several thousands of letters in length.

Dr O'Kane mentioned the Tom Wahlig Foundation (http://www.hsp-info.de/en.htm) who research HSP and promote an international network of HSP researchers.

AGM2015: The differences between pure and complex HSP - Prof Henry Houlden

Professor Henry Houlden works at the National Hospital for Neurology and Neurosurgery, in London. His presentation covered three areas:

• The differences between pure and complex HSP
• Genetics and genetic testing
• Shared network and genome sequencing 

Prof Houlden reminded us that HSP is generally described with increased stiffness, muscles becoming weaker and a slow progression. For pure HSP the three main areas are legs, bladder and the back. Pure HSP can also affect spasticity in other areas (including the upper body), but if there are other symptoms present then this becomes complex HSP. There is some variation in what symptoms might be expected, but these might include balance. A few videos were then shown with some examples.

If there is not a clear family history then an MRI scan of the brain and the spinal cord can help the diagnosis. For example, if there are some symptoms and compression in the spine this is not HSP and can be treatable. If the initial scan reveals that HSP is a contender, then blood an be sent for genetic testing, and tests on parents/siblings (etc.) can help in a better identification.

The scan would also show up the corpus callosum (a thick band of nerve fibers that connects the left and right sides of the brain allowing for communication: transfer of motor, sensory, and cognitive information). A thin corpus callosum occurs in some complex forms of HSP. For patients with complex HSP a repeat scan every 5 years would help to measure progress/change over time.

Some patients also experience problems with their feet - for example blisters and high arches (blisters can be a problem for people with HSP and diabetes http://www.nhs.uk/Livewell/foothealth/Pages/Diabetesandfeet.aspx) Examination of these can lead towards a diagnosis.

Prof Houlden indicated that about 30% of HSP diagnoses are not genetic. Simply, not all of the genes which cause HSP have been identified yet. There are some 25,000 genes in the body, and currently (Feb 2015) 74 different HSP genes have been identified. Getting the correct diagnosis can give you confidence - there is confirmation of what you have, and the course of can be anticipated - including potential complications. 

The most common pure HSP types with dominant inheritance are SPG4, which accounts for about 40% of cases, SPG3A which accounts for some 2-3% of cases and SPG 31 which accounts for some 1-2% of cases. The most common complex HSP types are SPG11, SPG7, KIF5A (also known as SPG10) and SPG 35. Prof Houlden did not give prevalence information. 

Types of HSP which have a dominant inheritance pattern carry a risk of 50% of passing HSP to the next generation (assuming only one parent carries the gene). Each child has an equal risk of inheriting the gene. For types of HSP which are recessive, the risk of passing the gene to the next generation is tiny, unless both parents are from the same family. Tests can be done prenatally, by CVS (Chorionic villus sampling) at about 10.5 weeks or by amniocentisis at about 16 weeks - however both tests carry risks of miscarriage and/or infection. Alternatively, Pre-implantation genetic diagnosis can be used (like IVF) to check, however this needs funding and the permission of your GP.

Prof Houlden then talked about management of HSP, by reference to Spastin (SPG4). The main points were:

• Physiotherapy and orthotics
• FES (functional electrical stimulation)
• Baclofen
• Self catheter and Detrusitol (noting Detrusitol works best if the bladder empties fully)
• High walking sticks (these result in a more upright walking position)
• Hip and knee replacement later in life.

On FES, it was observed that relatively few people were using FES 3-4 years ago, and the uptake of this has increased more recently. FES is available for HSP in London, Sheffield and Salisbury.

Prof Houlden talked briefly about bowel issues. The effects are not predictable, and this cannot be used in differentiating between pure and complex HSP. Bowel issues can usually be treated.

Prof Houlden then talked about a potential link between HSP and dementia. There can be some cognitive problems later in the progression of HSP, including SPG4. Sometimes the brain has to focus on walking which it does at the expense of other processing. These problems may also occur as a result of fatigue - which increases as it becomes harder to do more, or they may be a side effect of medicaiton being taken. If there are mental problems with HSP then tools to help cognition may be of limited benefit. In this case it is better to treat the condition.

 A European HSP network is (being) set up, with the objective of sharing information, particularly clinical problems, databases of patients and blood/MRI results. This can help research and the treatment of HSP. The network is looking for biomarkers for HSP which could track the progression of HSP, the effects on bones and/or the benefits of drugs. There is more on biomarkers here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078627/. The shared database of patients can be used to help find candidates to take part in drug trials. It is likely that drug trials will be targeted to specific genes, and it becomes necessary to find a sufficient sample to determine the benefits of the drug.

Lastly, Prof Houlden covered getting access to services. Your GP is able to give a referral, and appointments can be booked using the choose and book system. He advised seeing a specialist in clinic once every few years, noting that it can be difficult for a local neurologist to be knowledgeable of rare diseases, but there is more money available for rare diseases at the moment, and this is leading to increased awareness.