A successful Annual Workshop was held at Concord Hospital on October 28th, 2007. Reports of the presentations are available via the links below or just scroll down.
HSP Developments– Update by Prof. Garth Nicholson
Detecting the causal mutation and predictive testing – Dr. Marina Kennerson on the new and first Australian HSP gene testing service
Self -Management & Treatment of the Symptoms of HSP – Discussion led by Frank McKeown
Towards control of HSP– President Robin Bligh on a new Project under consideration
Professor Graeme Morgan discusses genetic counselling.
A report on the presentation of Prof. Garth Nicholson, Neurogeneticist
There are opportunities for the HSP Research Foundation, as one of several mobility disability patient groups, to persuade Governments to give special attention to funding research which, in the longer term, can reduce Government subsidies. More important to mobility impaired people, the result would be more mobility and more productivity for the country.
The statement is based on the difficulty of raising research funds from the various Government and Government supported funding groups, against competition from other organizations that pursue funding for more well known illnesses.
Current treatments are aimed at stopping or at least slowing progression with physical therapy and appropriate surgery to improve mobility. Some may think that because there is no tablet or injection that there is no treatment. That is not correct as the treatments just mentioned are making a difference to people who use them.
HSP diagnostic testing in Australia is now up and running with tests available for finding and typing mutations in three major genes. The research leading up to these tests included 5 families for which the new tests matched the results in European tests. These tests now need to be confirmed in our diagnostic laboratory with another blood sample.
Recent developments include the use of adult stem cells collected from a simple nose biopsy at the top of the nose. This provides blood with olfactory stem cells which are actually central nervous system cells.
Research is currently being undertaken in Queensland where these stem cells are being differentiated in to target cells and grown for nerves that may replace damaged nerves. Prof. Nicholson considers it unlikely that long nerves will be replaced by stem cell therapy. Regenerating a long spinal nerve all the way to the foot is unimaginable. However a very important role of stem cell science is that it opens up the opportunity to study different mutations in their own stem cell lines as stem cells can be differentiated into the type of cell to be studied.
Prof. Nicholson explained and illustrated the workings of a nerve cell including the important role of transmitter of electrical impulses. The impulses are transmitted for communication to other nerve cells via axons which are part of nerve cells. For example, the mitochondria in the cell body supply the electrical charges, but with the HSP mutation, spastin, these charges fail to be transmitted. This is because the ‘railway lines’ (microtubules) have broken down. Research into HSP cells must continue because these peculiarities need to be understood before a therapeutic drug can be discovered.
HSP involves about 30 genes and hundreds of mutations. More advanced technology will speed up research due to rapid screening using computer chips with known mutations already entered on the chip. There will be a need for collaboration among scientific institutions so specialization on different genes can take place and improve overall efficiencies.
Management of HSP can be improved in the areas of symptomatic and pre-symptomatic counselling, counseling regarding reproductive issues and antenatal testing. Support of the HSPers physical and social environment to help maintain independence also has to be improved.
Future treatments may be:
- Replacement products – eg ‘factorV111’ replaces some dysfunctional elements in haemophilia patients
- Block products – that may block the effect of a genetic defect
- Pharmacological treatment – a drug that overcomes the effects of the mutation to allow the system to work normally
- Gene therapy – replacing the faulty gene
- Stem cell therapy – some diseased or damaged tissues could regenerate.
A central registry of gene mapping and a library of mutations is needed and diagnostic testing needs to be global to further improve efficiencies.
ANZAC Research Institute
Dr. Marina Kennerson, Principal Hospital Scientist in Genetics
What is a gene?
A gene is a segment of DNA that codes for the synthesis of a protein. We can think of a gene as a paragraph of three word sentences that tells us information. The paragraph can be broken up into sentences (exons) and the sentences can be broken down into three letter words (codons which tell us the amino acids used). Amino acids are the building blocks of a protein. All genes begin with a start codon and end with a stop codon.
The sun was hot. The man did not get his hat. The hat was old.
Start codon Stop codon
We can think of genes being made up of sentences with three letter words (amino acids) that provide information about protein.
Genes contain exons:
The sun was hot. The man did not get his hat. The hat was old.
Each sentence represents an exon:
Exon 1The sun was hot.
Exon 2 The man did not get his hat.
Exon 3 The hat was old.
What is Gene Testing?
A genetic test is the analysis of human DNA, RNA, protein or certain metabolites in order to detect alterations related to a heritable disorder.
When you have agreed with your doctor to have a gene test the doctor willdecide which gene or genes to have tested for the presence of a mutation. The diagnostic laboratory detects and describes the mutation in the gene nominated if a mutation is present.
Types of Testing
- Confirmational diagnosis of symptomatic individual
- Predictive testing
- Predict possible future illness
- Predict carrier state in individuals whose children might be at risk.
What mutations can occur?
The sun was hot. The man did not get his gat. The hat was old.
The sun was hot. The man did not old.
The sun was hot. The man did not not get his hat. The hat was old.
The sun was hot. The did not get his hat. The hat was old.
HSP Gene Testing – Prevalence
The following table shows approximate prevalence of the 3 genes for which tests are available via Molecular Medicine Laboratory at Concord Hospital, Sydney.
Spastin (16 exons) SPG4 ~45%
Atlastin (13 exons) SPG3A ~10%
NIPA1 (5 exons) SGP6
Mutation Discovery by DNA Scanning
- Spastin & Atlastin
oHigh Resolution Melt (HRM) – Missense, Nonsense, small insertion, small deletion
oMLPA* – Exon Duplication, Exon Deletion
oHigh Resolution Melt (HRM) – Missense, Nonsense, small insertion, small deletion
- Known mutations in spastin, atlastin, NIPA1
- Multiplex Ligation-dependent Probe Amplification
of the Symptoms of HSP
A discussion led by Frank McKeown
Many HSPers in different countries recognise a significant and worthwhile difference in their mobility and functionality when they undertake regular movement and exercise. The factors most common in their descriptions of the effects of HSP are different combinations of:
- Spasticity, and
The regimes they undertake commonly seek to maintain or improve:
- Muscle relaxation, and
The exercise regime and focus of these activities varies quite a lot from individual to individual depending on many factors predominantly:
- Stage of development of their HSP symptoms
- Type of therapist they consult, if any, based on the individual therapist’s approach
- Individual preferences – trial and error, what works best; beliefs, motivation, and so on
- Access to, availability and affordability of resources, infrastructure and support. This varies from country to country, culture to culture and place to place – whether it be gyms, hydrotherapy pools, therapists, medical facilities and services, subsidies and insurance, lifestyle adaptations in the home, vehicle, workplace or community – even climate – are all relevant factors.
The majority of HSPers attending this session indicated that they regularly do exercise aimed at maintaining or increasing their mobility and functionality. They generally report a significant positive effect from it – ranging from 4 to 10 out of 10 on a subjective self-rating scale compared with not exercising. This is consistent with the reported experience of HSPers in the USA.
A DVD from the German HSP group was then shown, demonstrating physiotherapy programs specific to 3 individuals at different stages of HSP symptom development:
- Non-ambulatory [wheelchair]
- Walking with a support frame
- Walking independently
The DVD is now available for purchase with the suggestion of sharing with a physiotherapist as an aid to developing and tailoring individual programs.
HSP is not widely known or recognised by Australian physiotherapists. There are currently no clinical practice guidelines on HSP treatment for physios.
Note on Session Facilitator: Frank McKeown is not a medical professional and does not have HSP. He has a close friend of 20 years who does. He is a biological scientist and has been accredited and actively involved with the Australian Sports Medicine Federation over many years, including working with physiotherapists in multi-disciplinary teams. He has an abiding interest in the role and place of exercise in maintaining and improving HSPers mobility and functionality.
Robin Bligh, HSPRF President – on a new project under consideration
We have developed tests for 3 important genes and these will be available in November. It is now time to start switching research priority to finding an HSP cure (no, not utopia) finding a therapeutic drug with the help of stem cell research.
Stem cell science will enable scientists to demonstrate (without experimental animals) the growth of cell lines developed from CNS (central nervous system) stem cells from HSP SPG4 patients on the one hand and from unaffected people on the other. The purpose is to observe the biological differences.
Your Australian HSP Research Foundation has developed a proposal in conjunction with the National Centre for Adult Stem Cell Research (NCASCR), centred at Griffith University in Queensland, to conduct a Pilot Study aimed at:-
- Growing and maintaining CNS (olfactory) stem cell lines
- Differentiating them to other nerve cells
- Defining biological differences in the HSP SPG4 cell line from the unaffected cell line.
The proposal involves the use of adult stem cells as disease models. Even though adult stem cells are ideally suited for use in cell transplant therapy because there is no patient rejection, this proposal does not encompass cell regeneration.
The study is to last 12 months and cost $100,000. Upon achievement of those goals it means that Griffith University will make an NHMRC submission for a grant to identify and validate a Drug Target.
Then, knowing the Drug Target, the next stage is to screen thousands of compounds from the Griffith Uni compound library using modern high throughput screening methods to find active compounds that could be developed as therapeutic drugs.
Ten years ago we were saying “wish we had a therapeutic drug” and we are still saying that. Is it time to make a start or should we wait another 10 years?
If the long term goal of finding, proving and developing a therapeutic drug is successful then it can benefit HSPers the world over. Consequently your HSP Research Foundation put a collaborative proposal to the HSP group in 9 different countries. Interest has been expressed by 2 countries and we are now developing a more definitive proposal in conjunction with the NCASCR towards a collaborative project that would share the scientific outcome and the cost. This is still in progress.
A report on the presentation of Professor Graeme Morgan, Clinical Geneticist
Professor Morgan led the group through the story of the place of genes in inheritance, the combinations of genes that influence inheritance and the value of genetic counselling and gene therapy in preventing the transfer of inherited disorders.
Genetic inheritance was first studied by Mendel in 1865 although it was not acted upon until early 20th century.
Offspring inherit a gene from each parent and depending on the characteristic of each of those genes the child has various risks of developing the quality of that gene.
The gene can be autosomal dominant, and if ONE parent has the gene there is a fifty percent chance that the child will be affected, multiple generations will be affected and either sex could be affected.
If the gene is autosomal recessive there is a 25% chance of the child being affected. BOTH parents need to have the gene. They would not have the disease but would be carriers. It rarely affects other branches of the family unless cousins marry.
X-Linked inheritance is carried on the female’s X chromosome and is sometime found in multiple generations and is sometimes an isolated incidence. The female is generally unaffected or less affected and it cannot be transferred from the father to a male child to male.
A genetic study based on gene tests gives:
1.Opportunity for the prediction of likelihood of the disease occurring.
2.Confirms diagnosis when symptoms appear.
3.Aids prognosis at the onset of symptoms.
4.Enables people at risk of having affected children to have unaffected children.
If the case is an isolated one, the understanding and isolation of the genes helps to establish how it was inherited.
The isolation and identification of the gene of affected persons can enable those at risk of having afflicted children plan to avoid having such children. The young people should make their own decision in such instances.
Professor Morgan delicately and caringly handled the issue of pregnancy planning which becomes available with the development of successful genetic testing and identification. There are currently two procedures, one for a pregnant woman and the other pre–pregnancy, each with their advantages and disadvantages.
1. PND – Pre-natal Diagnosis
When an at-risk woman becomes pregnant, at 11-12 weeks a relatively simple procedure for the mother can reliably ascertain the HSP status of the pregnancy. While the advantage of PND is that there is already a natural pregnancy, the disadvantage is in having to contemplate termination of that pregnancy.
2. PGD – Pre-implantation Genetic Diagnosis
Using the procedures of In vitro fertilisation (IVF), eggs are fertilised and tested for the mutated gene. If successful, one clear embryo is transferred to the mother and others are retained in the freezer for their future use. The advantage of this procedure is that a successful pregnancy almost certainly produces an unaffected baby. The disadvantages are that the procedure is very stressful for the family and diagnostic accuracy is not claimed to be 100%. There is a 50% chance of a successful pregnancy and the cost is high. Testing for the mutated gene can now be done in Australia for mutations in the 3 major HSP genes.
Maternal age is a factor when making the choice between PND and PGD.
Over 40 hospitals throughout the country make Genetic Counselling available. The internet link http://www.genetics.edu.au/Genetics-Services/genetic-counselling-services gives public hospital location and genetic counselling phone number for accessing the Service.
With the availability of HSP gene tests in Australia thanks to the funding by HSP Research Foundation members and supporters there is light at the end of the tunnel and for the first time HSPers may have a choice.