HSP Research - Further Papers

This evening I have re-searched the link to see what else has been published since my previous update on papers in August 2012. Another 63 papers have been added since then, all published in 2012 or 2013.

Actually, the statistics look quite similar to those from last year. The search shows that there's been about 70 papers per year published each year since 2006, and the authors who were top of the table in terms of published papers have all had at least one paper published so far in 2013. The journals with the most papers published also have, on the whole, had an HSP paper published in 2013.

There are some 250 new researchers working in some aspect of or relevant to HSP since my last data update - by which I mean author names which had not previously appeared in any of the original data sets.

I'll look at the details of these papers and read their abstracts another day.

The link to get the search is here: http://www.ncbi.nlm.nih.gov/pubmed?term=((hereditary%20OR%20familial)%20AND%20%22spastic%20paraplegia%22)%20or%20%22strumpell%20lorrain%22.

Babinski’s sign - The 'tickle' test.

As part of my trawl of the symptoms of HSP, today I'm exploring Babinski's Sign, which seems also to be called Babinski's Reflex.

1) Babinski reflex is one of the reflexes that occurs in infants. It occurs after the sole of the foot has been firmly stroked. The big toe then moves upward or toward the top surface of the foot. The other toes fan out. This reflex is normal in children up to 2 years old. It disappears as the child gets older. It may disappear as early as 12 months. From: http://www.nlm.nih.gov/medlineplus/ency/article/003294.htm

2) The Babinski sign is an important neurologic examination based upon what the big toe does when the sole of the foot is stimulated. The Babinski sign is obtained by stimulating the external portion (the outside) of the sole. The examiner begins the stimulation back at the heel and goes forward to the base of the toes. A useful way to elicit the response that requires no special equipment is with firm pressure from the examiner's thumb. Just stroke the sole firmly with the thumb from back to front along the outside edge.

Too vigorous stimulation may cause withdrawal of the foot or toe, which can be mistaken as a Babinski sign. Most newborn babies are not neurologically mature so they normally show a Babinski sign. Upon stimulation of the sole, they extend the great toe . Many young infants do this, too, and it is perfectly normal. However, in time during infancy the Babinski response vanishes and, under normal circumstances, should never return.

A Babinski sign in an older child or adult is abnormal. It is a sign of a problem in the central nervous system (CNS), most likely in a part of the CNS called the pyramidal tract. From http://answers.yahoo.com/question/index?qid=20090509083919AAiuHmw

The next part of my trawl is to see what pops up from the HSP research papers. There are various papers from 1989 and more recently which note that Babinski's Sign is present in a number of cases of HSP (and similar conditions). Of note, there's a paper from 2000 which described a new locus for HSP in a french family, and compared these patients with familys with SPG4 noted that there were significantly more patients without Babinskis signs, 

This suggests to me that Babinskis sign may not be present in everyone with HSP.  And, therefore, I shouldn't start making bold assertions after tickling the feet of my family....

Of note, when I was having my blood test to determine if I had HSP back in early 2009, one of the things the people at Genetics said was that they might be able to tell if I had HSP by tickling my feet. So, I'm quite pleased to have found out what that means.

The 2000 paper is: A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Fontaine B, Davoine CS, Dürr A, Paternotte C, Feki I, Weissenbach J, Hazan J, Brice A. Am J Hum Genet. 2000 Feb;66(2):702-7. http://www.ncbi.nlm.nih.gov/pubmed/10677329

Symptoms Update - Stiffness

A few more months have passed since I last did a symptoms update. The 'problem' with a condition that acts slowly is trying to identify when something has changed. This time its more of a gut feel than a specific observation. I think it's more difficult to stand up, and I think its more difficult to stand with my legs straight for a long time.

This is a feeling over several weeks, so I dont think there are any particular circumstances which would give rise to this. My standing-with-legs-straight comment comes from one of my few multi-tasks - when I give our nearly-one-year-old his bedtime milk I stand with my legs straight, body bent over, and then move my hips to get a hamstring stretch (multi-task is stretching and feeding at same time). This has become more uncomfortable in the last week or two, and I've needed to stop the stretch for a moment and then come back to it, whereas a month or two ago I was able to hold the stretch for a whole bottle of milk.

Introduction to cell biology

When I met Dr Reid at Addenbrookes the other week he started to explain cell biology, and made me realise there's a large gap in my knowledge. At one level I know that I have a mutation in one of my genes and at the opposite level I know the end result of HSP. There's a huge gap in between.

My first thing to understand is the general function of a gene. In simple terms each gene carries the code to make a protein, and that protein has a particular job to do. When there is a mutation in a gene this can prevent the protein working properly. So, the importance of a mutation depends on how critical that protein is in keeping your body working.

I'll explore the protein side of things another day, and focus this time on how a mutation affects the manufacture of the protein.

Back a few months ago I found that my mutation was on Intron 12 of the Spast gene. Genes are made up of sequential blocks called Introns and Exons. There are two steps in making a protein - Transcription and Translation.

The transcription step the information in the gene is transferred into a separate molecule. The information that is needed to make the protein is from the Exon, so the transcription process involves joining all the Exon parts together and discarding the Intron parts. I'll explore the function of Introns another day. This function is called RNA splicing.

The translation step involves a Ribosome which reads the Exon sequence and uses the information to build the protein one amino acid at a time (amino acids are the building blocks of proteins). This reading and building process continues until a 'stop' instruction is reached and the protein is complete.

When there is a mutation in a gene the problem is that the Introns and Exons cannot be identified correctly, and the spliced set of Exons may contain some sections of Intron, have some parts of Exons missing or some other jumbled information. This means that the Ribosome cannot read the set of instructions correctly, and the protein is not made correctly. The body is good at checking what is made so an erroneous protein may not be made at all. If the protein is made then it may not function properly (which may mean that it works better or worse).  

I accept that this post is a bit heavy on the technical info, and I'll try and visit each of these steps again and provide some context.

Various links:
http://ghr.nlm.nih.gov/handbook/howgeneswork/makingprotein
http://en.wikipedia.org/wiki/Introduction_to_genetics
http://en.wikipedia.org/wiki/Proteins#Cellular_functions
http://en.wikipedia.org/wiki/Intron
http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/mutationscausedisease

Rare Disease Day

Well, today is rare disease day (http://www.rarediseaseday.org/), and I thought it was time to move a bit further out from the shadows and begin to link up my various on-line presences. Today I've:

• added my name to my blogger profile here, 
• removed the word "possible" from the blog header,
• joined HSP groups on facebook,
• added "herediary spastic paraplegia" to my twitter bio,
• added links here from my facebook and twitter pages,
• written an HSP post on my internal work blog.

So, social media, tick! On this front it is my intention to tweet about HSP things that occur to me. I realise that twitter may start to get a bit messy as I mix work and HSP things, but then that's the point of hashtags. I'm going to use #hspfsp for the condition and #hspjourney for this blog. @munkee74.

Yesterday I had the opportunity to meet Dr Evan Reid at Addenbrookes, Cambridge. My mum had an appointment with him and I went along with her. I learnt some interesting stuff there, and that will certainly form a post (or two) in the near future.

It comes as no surprise that the general advice is for people to stay fit, healthy and active. He noted that there are Paralympians who live in wheelchairs who are at the peak of their fitness. This observation reminded me of the recent HSP newslink front page article about Rebecca Hart, a Paralympian Equestrian from the USA. http://www.hspgroup.org/ 

1st March edit - I also decided at the end of the day to add a link and post on LinkedIn, completing my current set of social media profiles. Its been a very interesting 24 hours looking at my visitor statistics since all this posting/linking activity.

4th March footnote - What a busy few days! I'd like to thank people for their messages, likes and re-tweets, and for taking the time to read this blog.

HSP Research - Trawl Update

Time ticks by.

I've been reading abstracts and trying to categorise them. Today marks the completion of the 2012 papers retrieved so far (41) and the move into 2011 (5 papers), and I've also started working backwards, having done all papers with abstracts from 1976 and before (10 papers - earliest abstract from 1953).

The four papers which I've so far identified as the most interesting (yes, I know that's very subjective) are:


1) Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia. http://www.ncbi.nlm.nih.gov/pubmed/?term=22574173 Henson BJ, Zhu W, Hardaway K, Wetzel JL, Stefan M, Albers KM, Nicholls RD.

This paper identified the regulatory mechanisms controlling the expression of SPAST (therefore SPG4), providing new functional targets for mutation screening and therapeutic targeting in HSP.

2)  White and grey matter abnormalities in patients with SPG11 mutations. http://www.ncbi.nlm.nih.gov/pubmed/?term=22696581 França MC Jr, Yasuda CL, Pereira FR, D'Abreu A, Lopes-Ramos CM, Rosa MV, Cendes F, Lopes-Cendes I.

This paper investigated the extent of brain damage in patients with SPG11

3) Disease severity affects quality of life of hereditary spastic paraplegia patients. http://www.ncbi.nlm.nih.gov/pubmed/?term=21631647 Klimpe S, Schüle R, Kassubek J, Otto S, Kohl Z, Klebe S, Klopstock T, Ratzka S, Karle K, Schöls L.

This paper correlated Health-Related Quality of Life (HRQoL) with severity of HSP, concluding that quality of life deteriorates as symptoms progress. They recomended that HRQoL should be considered in trials.

4) Bladder dysfunction in hereditary spastic paraplegia: a clinical and urodynamic evaluation. http://www.ncbi.nlm.nih.gov/pubmed/?term=22289900 Fourtassi M, Jacquin-Courtois S, Scheiber-Nogueira MC, Hajjioui A, Luaute J, Charvier K, Maucort-Boulch D, Rode G.


This paper quantifies bladder problems for people with HSP.

More on urinating

A thought crossed my mind recently, remembering a trip to the north (of England) a couple of years ago where I happened to be in a public toilet  and spotted a sign suggesting that if you'd a number of symptoms similar to those that I described in my post the other week then you were advised to go to your Doctor/GP for a check-up as these were symptoms which could indicate prostate cancer.

So, I had a look on the NHS website and found:
http://www.nhs.uk/Conditions/Cancer-of-the-prostate/Pages/Symptoms.aspx
http://www.nhs.uk/conditions/Prostate-enlargement/Pages/Introduction.aspx

My conclusion is therefore, that if you've got any of these symptoms then a trip to the doctor is in order. It would be silly to self-diagnose and assume that its all HSP....

Symptom	HSP	Prostate Cancer
Urinary urgency	72.4%	Yes
Urinary frequency	65.5%	Yes
Urinary incontinence	55.2%	Yes
Urinary hesitancy	51.7%	Yes

Indeed the list is also "yes" in every line for prostate enlargement.

The risks are as follows:

Prostate Cancer: Prostate cancer is quite rare in men under 50. More than half of all cases are diagnosed in men over 70. Age is the most significant risk factor of all for prostate cancer. The older you are, the greater the risk. In old age, up to 8 out of 10 men have prostate cancer cells in the prostate. No one can give you an exact figure of risk. In the UK, about 1 in 9 men will get prostate cancer at some point in their lives. Remember, this is lifetime risk and involves men who get prostate cancer at any age, up to 85 or more. Your risk when you are younger is much lower than 1 in 9.
http://www.cancerresearchuk.org/cancer-help/type/prostate-cancer/about/prostate-cancer-risks-and-causes

HSP: Unfortunately the abstract of the HSP paper in my previous post doesn't give details on age. 80% of HSP patients appear to have some kind of issue.

Prostate Enlargement:Prostate enlargement is a common condition that is associated with ageing. Around 60% of men who are aged 60 or over have some degree of prostate enlargement.

Pes Cavus - Arched/High Foot

In part of my reading around I realised that I've spotted many references to "Pes Cavus" in HSP articles, and I didnt know what it was, so time for a quick trawl.

Pes Cavus has a range of other names: high instep, high arch, talipes cavus, cavoid foot, and supinated foot.  It's translation from latin is hollow foot.

Normally, when you stand up your foot flattens. If you've got pes cavus then it doesn't (or at least doesn't as much). This is the opposite of flat feet, and in the general population  pes cavus is much less common than flat feet. Diagram: http://docpods.com/high-arched-feet-pes-cavus-inverted-foot-types

Unlike flat feet, highly arched feet tend to be painful because more stress is placed on the section of the foot between the ankle and toes (metatarsals). This condition can make it difficult to fit into shoes. 

The high arch shape is either due to a tight or contracted plantar fascia (the tough sheet of fibrous tissue that runs along the sole of the foot) or due to a weakness in one muscle group causing unopposed action of the other, resulting in fixed plantar flexion of the foot (think pressing your foot on the accelerator or standing on tip-toes). I suspect that for HSP-ers it's the former of these. 

The symptoms are:

• Shortened foot length
• Difficulty fitting shoes
• Foot pain with walking, standing, and running (not everyone has this symptom)

The majority of this info came from here:
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002241/

There's a picture of someones feet laying in bed in a Google image search where their feet are pointing more along the bed rather than up in the air. I'm finding that my feet are tending to go in the same direction, so perhaps I'm heading for pes cavus myself.

Using my papers search I find from 1981:

Heel deformity in hereditary spastic paraplegia, by Rothschild H, Shoji H, McCormick D, in Clin Orthop Relat Res. 1981 Oct;(160):48-51. http://www.ncbi.nlm.nih.gov/pubmed/?term=7285436 


Varus deformity of the heel is often associated with, and may even precede the development of pes cavus. Clinical and radiographic examinations of the feet of members of three kindreds of hereditary spastic paraplegia, suggested that the autosomal dominant form manifests a significantly higher incidence and degree of heel varus deformity than the autosomal recessive  form of the disease. 



Various other web sites were mentioning pes cavus in realtion to Charcot-Marie-Tooth (CMT) and to Friedreich's ataxia, which come up in many of the HSP papers I've found.

Of course, I now have to look up Varus deformity as well, and I saw in passing several mentions of "hammer toe".....

...My-my-my-my music hits me so hard....

Review of 2012

Christmas is coming round again, and I thought I'd just review and summarise what I've discovered this year, and think about how different my symptoms are since the start of the year.

Knowledge:
The main knowledge change this year is the discovery of the PubMed database and the wealth of information  out there. I'm starting to digest this information (so there'll be no shortage of bits of info to post about!)

Symptoms:
My main observation this year is that I've spotted wear and tear on my shoes and in the car, so even if I didn't perceive it my symptoms must be getting slightly worse. I've also had the odd comment about 'limping'. I've also found that I need to keep exercising in order to keep my flexibility for a long as possible.

This Blog:
This year I've added an index and started to develop the blog so it's more than a list of posts. I've also started to become an "active" writer than a "passive" one, and I've joined various HSP communities. In the last month or so I've also started tweeting, and I think that 2013 will be the year where I join up my various on-line presences together.

The filming project:
In July 2011 I started my 'filming' project. I paused from that when our second son arrived, after about a years worth of footage. It is my intention to re-commence that project in 2013 as well.

The need to urinate (go to the loo)

Part of my digest of papers found a fairly recent one on the bladder side of the symptoms, and is my first look into this side of things. 
Title: Bladder dysfunction in hereditary spastic paraplegia: a clinical and urodynamic evaluation
Authors: M Fourtassi, S Jacquin-Courtois, M C Scheiber-Nogueira, A Hajjioui, J Luaute, K Charvier, D Maucort-Boulch and G Rode

Published in: Spinal Chord, Volume 50, Issue 7 (July 2012)

The link is here:http://www.nature.com/sc/journal/v50/n7/abs/sc2011193a.html.

I've only read the abstract so far, but the principal findings appear to be: a large series (29) of HSP patients were analysed. Ultrasound examination revealed no upper urinary tract complications.

Symptom	Pecentage	Patients
Urinary urgency	72.4%	21
Urinary frequency	65.5%	19
Urinary incontinence	55.2%	16
Urinary hesitancy	51.7%	15
Neurogenic bladder	82.7%	24
Detrusor overactivity	51.7%	15
Detrusor sphincter dysynergia	65.5%	19
Post-void residual >10% of voided volume	41.4%	12

This abstract gets quite "heavy" in its terms - so I've tried to find out what all of these mean, and I've described them below. My take on the paper is that more than 80% of HSP patients have some kind of urinary symptoms, the most common of which is "urgency" - a sudden need to wee. 

In order to allow a bit of self-diagnosis I tried to find out what is "normal". The bladder normally holds 400-600ml although the urge to urinate is usually felt at about 150 ml. Most people go to the toilet four to eight times a day. Most people can sleep for 6 to 8 hours without having to urinate. 


It would seem that bladder problems normally increase with age. Middle aged and older men often wake to urinate once in the early morning hours. Up to 35% of the female population over the age of 60 years is estimated to be incontinent. 17% percent of men over age 60 experience urinary incontinence, with this percentage increasing with age.


My attempt at describing the terms used: 
Detrusor - The bladder muscle
Urination is also known as micturition, voiding, peeing, weeing
Urinary urgency - is a sudden, compelling urge to urinate.
Urinary frequency -  the need to urinate more often than usual
Nocturia - the need to get up in the night to urinate
Urinary incontinence - any involuntary leakage of urine
Urinary hesitancy - a delay between trying to urinate and the flow actually beginning
Neurogenic bladder - dysfunction of the bladder due to disease of the nervous system or nerves
Detrusor overactivity - when the bladder muscle contracts unexpectedly during bladder filling
Detrusor sphincter dysynergia - instead of the urethral sphincter muscle relaxing completely during voiding it contracts causing the flow to be interrupted and the bladder pressure to rise
Post-void residual - the amount of urine retained in the bladder after urination.

As usual, most of my facts are courtesy of Wikipedia with a few other medical sites thrown in for good measure. Having written this I'm reminded of the two Ronnies I want to go to the lavatory sketch about going to the loo with the various smallest room, spend a penny references.... http://www.youtube.com/watch?v=HaGVQqVCJr4