New shoes

Once again I've got through another pair of shoes, so time to log the details here!

Actually, I've got through two pairs - my usual shoes and my biking shoes.

Usual shoes - this time I went for Hi-Tec Quadra Classic (low rise hiking boots). I got these at the end of November 2018, so they have done 18 months (1 year 6 months) before being too holey to wear.

The wear follows the same pattern - my left shoe is much more worn that my right shoe. The Hi-Tec's have performed better than my previous sketchers as the sole has remained attached to the shoe rather than detaching like the Sketchers had.

This time I considered getting another pair of Hi-Tec as they have worn much better than the Sketchers, but given that the time they lasted is about the same I have gone instead with Karrimor Supa 5 shoes.

The Hi-Tecs have lasted about as long as the previous Sketchers, suggesting that I'm on about 18 months per pair at the moment. Regular readers may note my preference to leave my shoes a little too long before replacing them!

You can see previous new shoe comparisons (with photos of old shoes) here:
https://hspjourney.blogspot.com/2018/12/more-new-shoes.html
https://hspjourney.blogspot.com/2017/05/shoe-wear-update-data.html

On the bike shoes front, I got my first pair of bike shoes with cleats in Sept 2017, and they lasted until December 2019:

Basically the soles were starting to detach, similarly on each foot. Equal wear isnt too surprising as these only get worn for walking for short periods. Those shoes lasted 2 years and 3 months. The current cycling shoes (also with cleats) are Shimano MT300.

An introduction to HSP

I needed a summary of HSP, and I was hunting around various support groups and social media pages, but none quite said what I wanted to get across, so I borrowed heavily from many sources and wrote my own:

What is Hereditary Spastic Paraplegia?

Hereditary Spastic Paraplegia (HSP) is a diagnosis which covers a large group of rare genetic disorders. HSP is a neurological condition, principally affecting the bodies longer muscle control nerves. There are upwards of 80 types of HSP which are generally inherited, with different types having different inheritance patterns. People with HSP can show their first symptoms at any age, although the most common ages of onset are in childhood (up to age 5) or in adulthood (age 35-50). HSP symptoms progress slowly over many years, and additional symptoms can develop as the condition progresses. HSP has several names, and is also known as Hereditary Spastic Paraparesis, Familial Spastic Paraplegia (FSP), Strümpell-Lorrain Syndrome, and some types of HSP have their own names.

Symptoms

The main symptoms are stiffness, spasticity or weakness in the lower limbs, leading to difficulties walking. There is large variation in both the speed of progression of HSP and in its severity (the amount HSP affects you). Some people may end up with mild difficulties walking. Others may be unable to walk and require a wheelchair most of the time. Those with HSP which significantly affects their mobility are likely to need different mobility aids as their symptoms change over time, and they may need various modifications at home or at work.

In addition to mobility issues many are affected by bladder problems, pain, and fatigue, and some will get numbness, tingling or other sensations. The effects of a person’s symptoms may vary from day to day more than their year-on-year progression. Life expectancy does not change for the majority.

Certain types of HSP are regarded as complex (affecting around 10% of people with HSP) and further additional symptoms may include problems with balance or coordination, learning/memory issues, problems with speech, vision, hearing or swallowing, problems with the skin, dementia, epilepsy or nerve damage. 

Diagnosis

As HSP is a rare disease (affecting around 3 in 100,000) it is not known by many medical professionals. The early symptoms of HSP are similar to other more common conditions and getting a diagnosis can be a long uncertain journey, potentially with several misdiagnoses along the way. Genetic testing is available for some types of HSP. Because there is such a wide range of potential symptoms, the speed of progression and ultimate severity are difficult to estimate for an individual.

Wellbeing 

It is difficult for people with HSP to get a clear picture how HSP will affect them over time, and plan for changes they may need to make, which can lead to feeling very uncertain about the future. Some with HSP are depressed, feel lonely, feel isolated or feel vulnerable. It is important for people with HSP to have a purpose in life and to take part in activities which they enjoy as these can help improve their wellbeing. It may be necessary to find new hobbies or interests as mobility changes over time. 

Treatment

At the moment there are no cures for HSP. Whilst there are many research teams looking into HSP around the world, all the current treatment is around symptom management. Someone with HSP may have a series of stretches and other exercises to do, they may take medication for spasticity, pain, their bladder and depression. Work on HSP is being done in many areas; to better understand how HSP works, to provide tools which can help assess HSP and its progression, to investigate new medicinal or other treatments, to explore genetic modification, and ultimately to identify if a cure can be found.

Support

There are various HSP support communities around the world which many with HSP enjoy participating with. The ability to share stories and experiences with others helps reduce feelings of isolation, and some groups also provide support in other ways. There are several support groups in Europe, mostly under the umbrella EuroHSP. There are other groups in the USA, Australia and Brazil. On-line communities include RareConnect, and there are numerous FaceBook groups and other social media groups.

Diagnostic Gap

There have been a number of papers in recent times which talk about a diagnostic gap in HSP. I wanted to explore what this means.

Many of you will know that the first identification of a gene for HSP happened in 1998. This was on the L1CAM gene, and was given the name SPG1. Since then more genes have been associated with HSP, and these have been numbered in order of discovery with sequential numbers, with the highest number (so far) being SPG82 identified in 2019 (https://www.omim.org/entry/618770#1). However, there is also a set of genes being identified which are associated with HSP, but which are not being given SPG numbers (for example, RNF170: https://www.genomemed.org/news/2019/10/28/new-gene-for-hereditary-spastic-paraplegia). The picture gets more complicated because there is genetic overlap between HSP (when considered as a whole) and Ataxia, ALS, Alzheimer's and Parkinson's.

An interesting question is: how many different HSP genes might there be? Different researchers have different ideas. Evan Reid suggested in 2014 that there may be 100-200 genes in total (https://hspjourney.blogspot.com/2014/08/agm-hsp-research-historical-perspective.html).

The paper: Perspectives on the Genomics of HSP Beyond Mendelian Inheritance by Dana M. Bis-Brewer and Stephan Züchner, (https://www.frontiersin.org/articles/10.3389/fneur.2018.00958/full) published in 2018 describes several key features. The text below is summary extracts of the paper (I basically copied the whole paper in and retained the parts I wanted to!):

It is usually assumed that eventually nearly all HSP patients will receive a single-gene diagnosis and the diagnostic yield of multigene panels has never been higher (albeit hindered by an increasing burden of Variants of Uncertain Significance).

However, most recently discovered HSP genes are rare causes of the disease affecting few people, and recent multi-patient gene testing studies have had less than 50% success rate in identifying an HSP gene. There is concern of a persisting diagnostic gap, estimated at 30–40%, and even higher for sporadic cases. Gene therapies may soon come to HSP, but these require a specific genetic diagnosis, which emphasises the need to fill the diagnostic gap, illustrated below: 

This gap may not be fully closed by classic Mendelian approaches. There are a number of strategies for identifying further Mendelian and non-Mendelian causes of HSP:

• Systematic reanalysis of unresolved cases can reveal new causative variants. The search should ideally be expanded beyond mutations in the protein-coding regions, but this requires whole-genome sequencing; 
• Another contributor of genome variability that could help resolve the diagnostic gap is structural variation, including copy number variations (CNVs), translocations, and inversions. CNVs are known to play an important role in HSPs, however determining whether a CNV is benign or pathogenic remains a considerable clinical challenge.
• Standard clinical genomic analysis focuses on typical modes of inheritance and unusual inheritance modes are often ignored. Inclusion of these can lead to successful identification of overlooked molecular diagnoses.
• Traditional Mendelian disease analysis are focused on specific alleles. These locus-specific studies disregard a more comprehensive genetic model for human disease in which variants of varying effect size as well as environmental influences contribute to disease.
• Contrary to general expectations for HSP families, asymptomatic carriers are not infrequent.
• Sex-dependent penetrance is suspected in some HSPs based on the excess of affected males.
• Given the high clinical variability observed across HSP patients, genetic modification of the primary allele has been anticipated.
• Exceptions to the fundamental “one gene, one phenotype” may occur. Here the primary allele is sufficient to cause disease, but a secondary allele is a “modifier” that controls aspects like disease severity or progression.
• The current classification systems suggest that HSPs are a distinct and isolated disorder, when in fact HSPs exist on a spectrum between inherited ataxias and Charcot-Marie-Tooth disease.
• These approaches increasingly require larger datasets which contradicts, of course, the low prevalence of rare disease. Raw genetic data aggregation may be the next frontier for HSP gene discovery.
• Gene therapy may soon be applied to specific HSP genes. These novel therapeutic approaches include gene replacement, antisense oligonucleotides (ASO), and soon gene editing. Most require a specific genetic diagnosis.