HSP Research - Updated Numbers

OK, so I've done some similar number crunching on the revised set of data as mentioned earlier in the month.

The search adds 553 papers to the 589 that were there before (there are 20 papers in the search where information doesn't appear to be complete, so I'm not including those for now)

The analyses were papers per year - which I've now graphed:

Number of papers per journal. This time I've restricted it to the journals where there have been at least 10 papers published, including "translations" to the full journal titles:

Number of Papers Per Journal

Journal Title	Papers	Most Recent
Neurology	66	2010
Journal of Neurology, Neurosurgery, and Psychiatry	47	2012
Journal of the Neurological Sciences	36	2012
neurogenetics	34	2012
American Journal of Human Genetics	33	2012
Archives of Neurology	30	2012
Journal of Neurology	29	2012
Human Molecular Genetics	28	2012
Journal of Medical Genetics	28	2009
Brain	26	2010
Rinsho Shinkeigaku (Clinical Neurology)	24	2011
Annals of Neurology	23	2010
European Journal of Neurology	22	2012
Clinical Genetics	22	2012
American Journal of Medical Genetics	21	2002
Movement Disorders	17	2011
Acta Neurologica Scandinavica	16	2009
European Journal of Human Genetics	15	2012
Human Mutation	14	2011
Human Genetics	14	2010
Brain and Nerve / No to Shinkei	12	2003
Neuromuscular Disorders	10	2009

These additional papers add more names to the researchers list, there now being over 4,400 researchers. The number of authors with more than 10 papers published goes up from 39 to 64. This list now looks like this:

Authors of at least 10 papers

Author	Papers	1st Yr	Last Yr	Papers 1st Auth
Brice A	47	1996	2012
Stevanin G	38	1995	2012	4
Fink JK	29	1995	2010	13
Reid E	27	1997	2012	11
Durr A	26	2000	2012	1
Hazan J	23	1993	2010	4
Crosby AH	22	2001	2010	1
Schöls L	22	2002	2012
Dürr A	21	1994	2009	2
Rouleau GA	20	1989	2012
Fontaine B	20	1994	2010	2
Blackstone C	19	2003	2012	2
Santorelli FM	19	2000	2011	1
Klebe S	18	2004	2012	6
Hedera P	18	1999	2011	10
Schüle R	17	2006	2012	6
Auer-Grumbach M	17	1999	2012	1
Pericak-Vance MA	16	1994	2012
Beetz C	16	2004	2012	7
Warner TT	16	2001	2011	1
Nielsen JE	15	1997	2011	4
Bernardi G	15	1993	2012
Tessa A	15	2000	2011	2
Klimpe S	15	2002	2012	2
Rugarli EI	15	2002	2012	1
Kawarai T	14	2002	2011
Depienne C	14	2006	2012	4
Forlani S	14	2006	2011
Hutchinson M	14	1997	2009
Proukakis C	14	2002	2011	4
Orlacchio A	14	2002	2011	9
Casari G	13	1998	2009	2
Weissenbach J	13	1993	2007
Elleuch N	13	2006	2010	2
Deufel T	12	2000	2009
Paternotte C	12	1996	2007	1
Patton MA	12	2001	2010
Boukhris A	12	2007	2011	4
Rainier S	12	1998	2008	5
Sperfeld AD	12	2004	2010	3
Patel H	12	2001	2008	3
Coutinho P	11	1996	2012	1
Bruyn RP	11	1990	2009	6
Bouslam N	11	2005	2007	2
De Jonghe P	11	1996	2012	1
Bertini E	11	1998	2011	1
Martinuzzi A	11	2003	2012
Feki I	11	2000	2011	1
Filla A	11	1998	2010
Kassubek J	11	2004	2012	1
De Michele G	11	1998	2011	1
Shen L	11	2004	2011
Azzedine H	10	2000	2012
Bassi MT	10	1999	2012
Tang BS	10	2001	2011	1
Tallaksen CM	10	2001	2010	2
Ruberg M	10	2003	2009
Iwabuchi K	10	1990	2008	7
Patrono C	10	2000	2010	2
Kobayashi H	10	1995	2003	3
Burgunder JM	10	1996	2010	1
Zatz M	10	1976	2010	1
Goizet C	10	2006	2012	4
Prud'homme JF	10	1996	2007

The top three most published authors remain the same as in the first set of results - A Brice, G Stevanin and JK Fink, but there are other authors appearing in the updated "top ten". I believe that  "Dürr A" should be "Dürr A" which I think is the same person as "Durr A", which would have been first last time, and equal first this time. Another avenue of data cleansing opens....

The latest search is this: http://www.ncbi.nlm.nih.gov/pubmed?term=((hereditary%20OR%20familial)%20AND%20%22spastic%20paraplegia%22)%20or%20%22strumpell%20lorrain%22. There is only one paper which was in my first search which was not returned in this later search. I'll leave the why of this for another day.

Updated search results - more papers!

Having started to look into the PubMed results a bit more, I wondered if I could find any references to those original Strumpell and Lorrain papers, and started searching around for them.

No joy, but I did manage to find some earlier papers on HSP/FSP, and I realise that the search I was using is limited.

So, the previous search: http://www.ncbi.nlm.nih.gov/pubmed?term=%22Spastic%20Paraplegia,%20Hereditary%22[Majr] now reveals 599, suggesting another 10 papers have been added. The earliest paper is from 1978, which I now realise means theres not far off 100 years worth of potentially published research missing.

So, I've spent a while messing about trying to get better results. It seems there's a balance to be struck. For example, a simple search on spastic paraplegia reveals some 17,000 results, and thats because the simple search brings back every paper with both words somewhere in the entry.

A better search result happens when you put quotes round "spastic paraplegia", giving some 1500 results. If the term "strumpell lorrain" is added you add a few more, including some back to the late 1800's.

However, its clear from browsing some of the abstracts that not all of these appear to be obviously relevant, so I added in the words hereditary and familial to the search. This gives a total of 1162 papers. Search here: http://www.ncbi.nlm.nih.gov/pubmed?term=((hereditary%20OR%20familial)%20AND%20%22spastic%20paraplegia%22)%20or%20%22strumpell%20lorrain%22. Earliest paper - 1946.

Next stage - to update my previous analyses of data and find out the most popular journals, years of research and published authors. Note - I have a feeling that this will end up being an iterative process, so I think I'll post this data on a page rather than in a post.

Current Research Highlights

I was having a read around the other week, and I found a link on the rareconnect website to this article:
http://www.sp-foundation.org/content/articles/State-of-HSP-Research.pdf

The article, written by Allen Bernard (whose daughter has HSP), is based on his discussions with five of the world's leading HSP researchers: 

• Dr. Craig Blackstone at the National Institutes of Health in Bethesda, Maryland; 
• Dr. Evan Reid at the University of Cambridge in the UK;
• Dr. Gerardo Morfini at the University of Illinois, Chicago;
• Dr. Joanna Bakowska at Loyola University, Chicago; and 
• Dr. Michael Hanna at the Texas A&M University, Commerce.

Of course, its difficult to abbreviate a 13 page document into a single blog post, but here we go - I've lifted various paragraphs from the document here:

Researchers working on hereditary spastic paraplegia, better known as HSP, know more today than ever before. They are uncovering new linkages between the proteins that are at the heart of the disorder all the time. If you rewind the clock just five years, almost nothing was known about the proteins involved in HSP, how they interacted, what they did or why they did it. Since then much has been learned. If you go back 10 years, some of the proteins involved where just being uncovered. Go back 15 and HSP was almost a complete mystery.

One of things that HSP has going for it from a treatment point of view is the proteins like atlastin are fundamental to how cells work. Because of this, cell biologists are becoming increasingly interested in studying them so they can increase their knowledge of basic biology. This greatly expands the base of very smart people exploring what these proteins do and how they do it. For a very rare disease like HSP, this is like hitting a walk-off homerun because it opens the door to unlooked-for-discoveries by researchers outside of the HSP field that could lead to significant breakthroughs in how HSP is understood and treated.


Researchers are finding more and more targets - functions like axonal transport and structures called microtubules, for example - to focus on for potential treatments.  To find a 'wonder drug', you might think that money is the end all, but perhaps the biggest inhibitor to finding a treatment is lack of good animal models.


While HSP-like symptoms can be created in mice, for example, the phenotype that mice exhibit is less severe than in people and, therefore, harder to measure. Also, mice are just a few inches from head to tail while the cells involved in human HSP are up to a meter long. Mice also take a long time to mature. So when you work with mice, it can take up to a year or more for symptoms to show. 


That is why researchers often turn to fruit flies, which share the majority of their genes with humans (they just have fewer variations of them) and they reproduce very quickly so you can see results much sooner. But, fruit flies are not people. They can point you in the right direction; give you an idea of what to look for or what questions to ask but they won't serve as a stand in for us. 


Researchers like Dr. Morfini also work with squid since their axons can be removed, viewed under a microscope, and react to HSP similarly to our own. Squid have long been used to study other central nervous system (CNS) diseases like ALS and Parkinson's so a lot is known about their basic structure. 


This makes squid an important source of information since 99 percent of a motor neuron cell is actually made up of its axon. So axonal transport, or the movement of molecules and proteins up and down the long thin tube that is the axon, is also considered by many in the field to be an good place to look for a cause of HSP. Any disruption of this very finely tuned architecture could result in disease.


HSP could be a a "Gateway Disease," a disease that leads to treatments and cures for some of today's most intractable illnesses. There are  conditions like Charcot Marie Tooth Type 2b and some neuropathies (a loss of sensation in the feet and hands that can lead to amputations) that involve the same proteins as HSP and yet, on the outside, look completely different. This is the type of thing that gets researchers from other fields interested because there must be something very fundamental going on.

ALS and its cousin primary lateral sclerosis (PLS) also have something in common with HSP because of proteins. So, at some point in the future, a researcher in one of these fields or an HSP researcher could uncover a strong bond that could lead to a treatment for both. Multiple sclerosis (MS) is another disease where there appears to be some overlap but all of these connection need to be explored much more deeply.

Current research highlights:
Bone Morphogenic Protein (BMP) signaling


One of the more promising areas of research is being pursued by Dr. Reid at the University of Cambridge. He and his team are looking at something called the BMP signaling. While BMP stands for bone morphogenic protein, what's really important is it appears that atlastin (SPG3A), spastin (SPG4), maspardin (SPG21), spartin (SPG20), and NIPA1 (SPG6) are all part of the same functional pathway within the motor neuron. 


BMP signaling appears to play a key role in how axons grow and what they look like as they branch out into synapses. It is this distal end of the axon, the one at the base of the spine, that connects the neurons in your motor cortex to your legs. If BMP signaling causes HSP's symptoms, then you have a target to go after with drugs. Dr. Reid strongly believes this could be the case but more research needs to be done; particularly in animals; especially in mammals.



Endoplasmic Reticulum (ER)


Dr. Blackstone's work has led to the realization that spastin, atlastin, REEP1, reticulon2 and possibly NIPA1 are all involved in shaping a very important organelle inside the cell called endoplasmic reticulum (ER). And this is extremely important from a cell biology point of view because the ER sits at the heart of cell function and is believed to run the length of the axon.


Indeed, before the discovery of atlastin, no one really understood why the ER looked the way it did. Now, HSP has opened a window into this most essential part of the cell. A gateway, if you will, to this and many other areas of cellular function that are now better understood because of HSP.


Casein kinase  2 (CK2)



Working together, the research teams of Dr. Morfini and Dr. Peter Baas at Drexel University in Philadelphia have found a potential target for a treatment of SPG4, spastin. Like Dr. Reid, their findings are preliminary but, if they pan out, they might provide a new framework for the development of treatments that may help prevent motor neuron degeneration in HSP. 

Their findings indicate that the protein kinase CK2, which regulates the activity of other proteins, is abnormally activated by mutant forms of spastin. Abnormally activated CK2, in turn, negatively affects yet other proteins that are involved in the movement of materials along the axons in an important cellular process referred to as “axonal transport”



Like many other protein kinases, CK2 is a drugable target. What's exciting about Drs. Morfini's and Baas’s work is that CK2 has been studied for decades, so it is very well understood and there are currently cancer drugs in Phase I of the FDA approval process today to regulate it.

Another new arrival - and cord blood storage

An update - a couple of weeks ago my wife gave birth to our second son. Double trouble in a few years, I'm sure!

We repeated the decision that we took for our first son, and decided to get the cord blood stored again. As a reminder for the first decision: http://hspjourney.blogspot.co.uk/2010/07/blue-sky-thinking.html.

One of the things which the genetics team said back at the beginning was that if we had two children, one with and one without the condition, then (provided there was a treatment available) the stem cells of the one without may be more of use to the one with. This info now becomes relevant.

In case anyone is interested, we used cells 4 life http://www.cells4life.co.uk/. The process was much easier this time as they now offer a phlebotomy service too. If anyone is thinking of doing this, then as a referral from an existing customer gets you (and me) a £50 Marks and Spencer voucher. Drop me a line....

Naturally, the HSP angle is still in the blue sky thinking zone, but there may be other uses for these as we go. Only the passing of the years will tell.

Symptoms Update - Shoe wear and 'skid marks'

I think I've spotted the next part of my symptoms. A look at my shoes shows that the heel is starting to be pushed outwards. I think this means that my gait must be changing. Interestingly it is noticeable on my left shoe more than my right shoe. The effect is slight, and I've had these shoes for a while.

Just thinking, if my heels are starting to poke out, I suppose that my knees must be getting closer together. I base this supposition on the scenario that its a walking thing, each step pushes my weight out and I dont think that my feet are further apart. I cant work out if my toes are pointing in more, and I'll need to do some more observing.

I'll also keep a lookout on my other pairs of shoes, as it's just one pair at the moment.

Also, on a similar front, I've noticed that I now have 'skid marks' on the cill of my car door where my right foot has slid over rather than me lifting it over after sitting down. I've only just noticed these marks, which perhaps suggests that its a fairly recent thing, having had the car for getting on for four years.

Overall, My conclusion is that my symptoms are starting to progress, and my wife has also noticed that my walking appears more difficult when I am tired or carrying heavy weights (3 year old boy sized). I wonder how long I'll be able to claim "no significant symptoms"....

Researchers - Most published

OK, a bit more number crunching on the papers I downloaded. There are over 2500 researchers who have contributed to the 589 different papers - so that's on average some 4-5 people per paper. A list of 2500 researchers would be a silly thing to put here, so I've limited as follows:
* Anyone who has been an author on 10 or more papers
* Anyone who has been an author on 5 or more papers when the most recent paper is 2010 or later
* Anyone who has been an author when the most recent paper is in 2012

This gives 103 researchers, sorted by papers, last year, then name.

I haven't yet worked out how to convert the funny characters into proper letters. A later (potential) task for another day is to find a biography of each.

Researcher Details

Author	Number Papers	First Year	Last Year
Brice A	28	1999	2010
Stevanin G	27	2004	2011
Fink JK	23	1995	2010
Crosby AH	20	2001	2010
Durr A	19	2003	2011
Santorelli FM	16	2000	2011
Klebe S	15	2004	2012
Hedera P	15	1999	2011
Nielsen JE	15	1997	2011
Hazan J	15	1993	2007
Reid E	14	2002	2011
Fontaine B	14	1994	2010
Dürr A	14	1994	2009
Schöls L	13	2002	2012
Beetz C	13	2006	2010
Klimpe S	12	2002	2012
Rouleau GA	12	1989	2012
Forlani S	12	2006	2011
Pericak-Vance MA	12	1994	2011
Proukakis C	12	2002	2011
Tessa A	12	2000	2011
Warner TT	12	2001	2011
Elleuch N	12	2006	2010
Patton MA	12	2001	2010
Hutchinson M	12	1997	2009
Schüle R	11	2006	2012
Kawarai T	11	2002	2011
Orlacchio A	11	2002	2011
Sperfeld AD	11	2004	2010
Patel H	11	2001	2008
Kassubek J	10	2004	2012
Bernardi G	10	2002	2011
Boukhris A	10	2008	2011
Shen L	10	2004	2011
Bruyn RP	10	1990	2009
Deufel T	10	2002	2009
Rainier S	10	1998	2008
Bouslam N	10	2005	2007
Kobayashi H	10	1995	2003
Bertini E	9	2000	2011
Depienne C	9	2006	2011
Rugarli EI	9	2002	2011
Blackstone C	8	2005	2011
De Michele G	8	1998	2011
Goizet C	8	2006	2011
Tang BS	8	2003	2011
Xia K	8	2003	2011
Zhao GH	8	2003	2011
Marchuk DA	8	2001	2010
Tallaksen CM	8	2001	2010
Feki I	7	2007	2011
Martinuzzi A	7	2003	2011
Sauter SM	7	2004	2011
Burgunder JM	7	1998	2010
Truchetto J	7	2008	2010
van de Warrenburg BP	7	2006	2010
Klopstock T	6	2006	2012
Bassi MT	6	2003	2011
Boespflug-Tanguy O	6	2002	2011
Braschinsky M	6	2009	2011
Gross-Paju K	6	2009	2011
Haldre S	6	2009	2011
Houlden H	6	1998	2011
Jiang H	6	2004	2011
Langer T	6	2003	2011
Mannan AU	6	2006	2011
De Jonghe P	6	1999	2010
Filla A	6	1998	2010
Lossos A	6	2006	2010
Mostacciuolo ML	6	2000	2010
Yang Y	6	2000	2010
Otto S	5	2006	2012
Criscuolo C	5	2004	2011
D'Angelo MG	5	2006	2011
Denora PS	5	2006	2011
Gaudiello F	5	2004	2011
Mundwiller E	5	2009	2011
Svenstrup K	5	2007	2011
Wood NW	5	2001	2011
Ludolph AC	5	1998	2010
Mhiri C	5	2008	2010
Siddique T	5	1994	2010
Zatz M	5	2002	2010
Ki CS	4	2005	2012
Brais B	3	2006	2012
Rioux MF	3	2006	2012
Dion PA	2	2007	2012
Dupré N	2	2007	2012
Karle K	2	2009	2012
Lee ST	2	2010	2012
Lee WY	2	2005	2012
Ahn JY	1	2012	2012
Caplan JP	1	2012	2012
Cho JW	1	2012	2012
Kohl Z	1	2012	2012
Levert A	1	2012	2012
Noreau A	1	2012	2012
Osmolak AM	1	2012	2012
Ratzka S	1	2012	2012
Szuto A	1	2012	2012
Thibodeau P	1	2012	2012
Wallenberg RB	1	2012	2012
Yoon WT	1	2012	2012

Another community

In my search for different on-line HSP communities I found "patientslikeme". This site has an HSP community with 56 people with the condition.

Personally, I'm reluctant to join this community as they sell users information in order to make profit, therefore I'll just mention this for information.

http://www.patientslikeme.com/conditions/493-hereditary-spastic-paraplegia

Joining Communities

In the last few weeks I've changed my policy slightly - from a passive to an active contributor. 

Previously, other than telling my immediate family, I'd been staying silent about my blog. Naturally I'd been keeping my eyes out to see if had been popping up anywhere. And, until a month or two ago it seemed to be 'under the radar' then I spotted it on rarediseasecommunity - now called rareconnect.

So, I joined up with rareconnect, and posted a link to this blog: http://www.rareconnect.org/en/community/hereditary-spastic-paraplegia/article/link-to-my-fsp-hsp-blog

I also joined the hsp support group http://hspgroup.org/, and am starting off letting members know about this blog. With hindsight, I cant find a good reason why I hadn't sign up here earlier, but done now.

I'm not one for 'shouting from the rooftops', so this will be a gradual process.