Kennedy’s Disease vs ALS: How muscle patterns can aid diagnosis and perform as a novel biomarker

Researchers from University College London led by Dr Pietro Fratta and Dr John Thornton found that muscle imaging can help distinguish Amyotrophic Lateral Sclerosis (ALS) from Kennedy’s Disease based on the way specific muscle groups deteriorate in each condition. The method can also help assess the severity of the disease.

ALS is a rapidly progressing condition which affects both upper and lower motor neurones, leading to inability to move limbs and failure of breathing muscles at the later stages of the disease. The complex cause of this condition is not yet fully understood but is thought to be a combination of genetic and environmental factors. Kennedy’s Disease on the other hand is much slower in progression and severity and is primarily caused by a gene mutation.

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Kennedy’s Disease: focus on muscle damage reveals key biomarker

Findings from the largest biomarker study of people with Kennedy’s Disease, published in the journal Neurology, found a predictive biomarker to help in differential diagnosis and tracking clinical progression. Led by Dr Pietro Fratta from University College London, the research team highlighted the importance of markers of muscle mass rather than neuronal damage in Kennedy’s Disease, differentiating it from the slightly more common motor neurone disease (MND).

Kennedy’s Disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a rare genetic condition that leads to progressive weakening and wasting of muscles, particularly affecting the limbs and bulbar region. Caused by a mistake on the AR (androgen receptor) gene (positioned on the X chromosome), this condition mainly affects males, with a 50% chance of receiving the affected gene from their mothers (women can only be carriers of the genetic mistake without developing the disease).

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AMBRoSIA and NECTAR – Make your mark on MND

It has been almost a year since we announced that AMBRoSIA (A Multicentre Biomarker Resource Strategy In ALS) had begun to recruit participants (read the Autumn 2017 edition of Thumbprint).

AMBRoSIA is the biggest project that the MND Association has ever funded and recruitment occurs at three sites throughout the UK (Sheffield, headed by Prof Dame Pam Shaw, Oxford, headed by Prof Martin Turner and London, headed by Dr Andrea Malaspina).

The project will collect a number of biological samples, including blood, cerebrospinal fluid (CSF), urine and skin in order to identify biomarkers (markers of biological change) that could be a signature of MND.Read More »

Motor neurone signalling and the effects of RNA in MND

Dr Pietro Fratta completed his first MRC-MND Association Clinical Research Training Fellowship in 2014. Last year he was awarded a new £1.16 million Clinician Scientist Fellowship to continue his research at University College London, studying the earliest physical changes that affect motor neurons in MND (our reference 946-795). Our contribution to this four year research fellowship is £280,000.

Pietro Fratta
Dr Pietro Fratta, University College London

As his first Fellowship progressed, Dr Fratta became more interested in the field of RNA biology, where he is rapidly establishing himself as an expert. His latest project aims to see whether RNA plays a pivotal role in the earliest signs of cellular damage that occur in MND.

RNA is the cell’s copy of our genetic material known as DNA; Dr Fratta is hoping to establish if the transport of RNA molecules along the nerve fibres is impaired and if so, whether there are particular versions of RNA that are particularly important for motor neurone health and survival.

Several lab studies have shown that the process of transporting things up and down the motor neurones is impaired long before the physical signs of damage are seen. His research will seek to find out what RNA molecules are present in both the cell body of the motor neuron and the nerve fibres.Read More »

Raising the profile of Kennedy’s disease

Did you know the MND Association also supports people who have Kennedy’s disease?

In May a new clinic specialising in Kennedy’s disease opened in London at the National Hospital for Neurology and Neurosurgery.

To mark this big step in helping support and treat people with Kennedy’s disease, Katy Styles who campaigns on behalf of the Association, and whose husband Mark has Kennedy’s disease, thought it would be a great opportunity to raise awareness of this rare condition.

Katy and Mark Styles
Katy and Mark Styles

There is very low awareness of this disease amongst neurologists, healthcare professionals, the general public and within the Association itself. We do all we can to explain to everybody what Kennedy’s disease is and what it’s like to live with.

Due to the rarity of Kennedy’s disease you can feel very much alone. It is so great to be part of the MND family and the Association is key to this by making us feel part of a wider community.”

What is Kennedy’s disease?

Kennedy’s disease is a condition similar to motor neurone disease (MND) which affects motor neurones. It is sometimes called spinal and bulbar muscular atrophy (SBMA).Read More »

New fellowship awarded to further our understanding of RNA in MND

Dr Pietro Fratta (University College London) received his initial Training Fellowship through the MND Association/ Medical Research Council (MRC) Lady Edith Wolfson Programme in 2010. Starting on 1 February 2015, Dr Fratta was awarded a Clinician Scientist Fellowship to continue his research into MND.

LEWFP_Logo_BLACK

Totalling £1.16 million, of which the Association has committed to contribute £280,000, this new fellowship will allow Dr Fratta to find out what RNA molecules are present in both the cell body of the motor neuron, and the nerve fibres. Read More »

On the second day of Christmas MND research gave to me: Two new inherited MND genes

Boxing day is here, there’s still some leftover turkey but let’s not forget… it’s the second day of Christmas!

“On the second day of Christmas MND research gives to you… TWO new inherited MND genes”

dna2014 saw the discovery of two inherited MND genes, the first being MATR3 in March and the second being TUBA4A in October. We will be discussing TUBA4A in a later blog post, but for now, here’s what we know about MATR3:

The MATR3 inherited MND gene discovery has provided us with further evidence that abnormal RNA processing is involved in MND.

The MATR3 protein, which is produced from the MATR3 gene, is commonly found in the nucleus or ‘control centre’ of the cell and is involved in the processing of RNA (the cell’s copy of DNA that is responsible for making new proteins). RNA processing has been previously associated with other inherited MND gene mutations (eg TARDBP and FUS). The MATR3 mutation also affects this process, adding more evidence to the role of abnormal RNA processing in MND.

Click here to read more about MATR3 here

Matrin 3 gene identified

Following on from our ’year of hope’ appeal last month an international team of researchers, including two funded by the MND Association, have identified mutations in the Matrin 3 (MATR3) gene as a cause of the rare inherited form of MND.

Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Clinical Research Fellow Dr Pietro Fratta was involved in the research, which was published on 30 March 2014 in the prestigious journal Nature Neuroscience.

Inherited MND is a rare form of MND (5-10% of total MND cases) and the MATR3 gene is the latest to be identified. This rare form of MND is characterised by a family history of MND.

New gene, new gene

When a new gene is first identified this creates a great deal of ‘buzz’ amongst the MND research community, often generating more questions than answers:

  • How common is this inherited MND gene?
  • How does this gene cause MND?

This is the starting point for MATR3. Unfortunately, we just don’t know the answers to these questions at the moment. Hopefully MND researchers will now use the discovery of MATR3 to find the answers to these questions and further our understanding of this gene.

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Unravelling TDP43 toxicity

Background to TDP43

A characteristic sign of motor neurones affected by motor neurone disease is the clumps of protein visible down a microscope. Although these proteins have been observed in motor neurones from people affected by MND since the earliest descriptions in the 1870s, a key discovery was made when the identity of a protein, common to all types of MND, was unveiled as ‘TDP43’ in 2008.

Two years later a second protein called FUS was also been found to be common to all types of MND. More information on this aspect of MND can be found in an article on our research blog.

One of the exciting things about these two discoveries was that they were both linked to a set of biological pathways, known as RNA processing. The was the first major clue that RNA processing was involved in MND. When the discovery of genetic defect in the C9orf72 gene came along in 2011, that made a third MND-causing gene defect that linked to RNA processing.

The first session of the 24th International Symposium on ALS/MND after lunch yesterday was dedicated to the topic of RNA processing and dysregulation. Several of the talks presented work on understanding the role of TDP43 in MND.

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Jolly Good Fellows!

There’s a scene in the 1969 film Battle of Britain where Laurence Olivier, who plays the Air Chief Marshal, is in a meeting with his two Vice Marshals. One of them complains that they don’t have enough planes; the other is more concerned with keeping the airfields working. Olivier silences them both by telling them that the fight will be won or lost on one key factor – the number of trained pilots.

It’s a rather cheesy film, but I used that story earlier this month to illustrate the importance of investing in bringing through the next generation of researchers in our battle to defeat MND.  We organised a ‘get together’ of our Lady Edith Wolfson Clinical Fellows at the Sheffield Institute for Translational Neuroscience (SITraN) to share their research findings with the donor who has so generously supported the scheme. The ‘get together’ also provided a wonderful opportunity for them to exchange information and expertise with each other, as well as all the staff of SITraN, who over the course of the day were frequently shuttling between the lecture room and their labs.

The Fellowships are aimed at attracting and training the brightest and the best Clinician-Scientists (or ‘Doctor-Doctors’ as I sometimes call them – with both a medical degree and a science PhD). Even so, I couldn’t resist using this cartoon in my introduction, although the reality is very different for our Fellows – the bar is set very high and even applicants for the Junior Fellowships need to have considerable research experience and be fully ‘lab tested’.

image courtesy of www.vadlo.com
image courtesy of http://www.vadlo.com

Our host for the day was one of the world’s most respected MND ‘Doctor-Doctors’, SITraN Director Prof Pam Shaw, who welcomed everyone to the meeting and provided an overview of the multidisciplinary expertise and collaborative philosophy that underpins SITraN. Prof Shaw also has a great belief in the importance of nurturing the next generation of talent and it is no surprise that almost half of the Clinical Fellows in the programme are based at SITraN.

Are fit and active people more likely to develop MND?

Our first research presentation was from Dr Ceryl Harwood (Sheffield) who is carrying out research on the epidemiology of MND. Specifically, she is addressing the question of whether physical activity is a risk factor for MND. As she explained, this has been a long standing theory, showing us a quote from a medical journal written over 50 years ago which stated:

”Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases”

She outlined the plausibility that physical activity may contribute to a complex interplay between biological and genetic processes that may predispose an individual to develop the disease. Generating the evidence, however, is no easy matter, but she has developed and validated a novel questionnaire to measure physical history in adulthood, using data from a diabetes study in the 1990s where over 1,000 people had detailed measures taken of their actual energy expenditure.

A hundred of these participants have recently agreed to undergo rigorous face-to-face interviews and their responses were correlated with actual physical measures from over 15 years previously. In other words, she can now assess how accurately peoples’ recollection of their physical activity – both day to day work and vigorous exercise – links with their actual energy expenditure at the time. This questionnaire is now being used to compare the physical activity profiles in up to 350 people with MND and 700 control participants in Yorkshire and surrounding counties.

Should the results support the theory that physical activity is a predisposing factor in MND, she will be perfectly placed to delve into the genetic factors that underpin the selective vulnerability of motor neurons.

Repetition is bad….

Dr Pietro Fratta
Dr Pietro Fratta

Next up to the lectern was Dr Pietro Fratta, (University College London) who has been immersing himself in the mysteries of how the C9orf72 gene can cause neurodegeneration – especially MND and a related condition called Frontotemporal Dementia (FTD).

Like a needle on a vinyl record can sometimes stick and repeat the same fragment of music again and again, this gene sometimes carries a repeat in its genetic code – specifically with the letters GGGGCC occurring again and again.  Dr Fratta has examined many DNA samples from MND and FTD patients and finds that these ‘repeat expansions’ are very large indeed, occurring between 700 and 4000 times!

The process through which these repeat expansions cause nerves to die is still a mystery, but Dr Fratta showed results from his lab which suggests that rather than losing its normal function, the C9orf72 gene gains some additional activity, turning it into a ‘rogue’ gene. He and his colleagues have recently shown that the repeat expansions can lead to the formation of very stable chemical structures called G-quadruplexes that have been implicated in causing nerve damage in other disorders.

He is currently studying how these structures interact with other cellular components, interfering with normal neuronal function. He is also starting to look at possible therapeutic approaches in a collaboration with the UCL School of Pharmacy to develop compounds that will bind to and hopefully inactivate these structures.

Over lunch, we were given a guided tour of the superb SITraN labs by Prof Shaw. Although I strongly believe that research is only as good as the researchers doing the work, there’s no doubt that having a purpose built institute filled with state-of-the art technology certainly doesn’t do any harm!

Then it was back into the lecture room for our afternoon presenters.

A Sheffield double act

The post-lunch session was kicked off by Dr Robin Highley, a neuropathologist who has recently completed his Fellowship and now divides his time equally between pathology duties and MND research. Dr Highley’s area of expertise is in how neurons edit the genetic instructions into precise ‘blueprints’ to make proteins, the essential building blocks of every cell in our body.

He used an entertaining analogy of making dresses form a pattern to describe the process of how DNA is made into RNA copies which can be ‘tailored’ into slightly different protein designs (to find out more about how DNA makes RNA and subsequently proteins see our earlier blog post).

Dr Johnathan Cooper-Knock
Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Using a variety of approaches he has looked at gene expression (which genes are being switched on and off) and gene splicing (how the RNA copies are edited) patterns in both inherited and non-inherited MND, as well as in non-MND states. He finds changes occurring in thousands of genes, but by performing searches on databases of the ‘function’ of each gene he can then sort them into different groups (which are then involved in key cellular processes). This provides important clues as to which cellular pathways are altered in MND, which will help researchers around the world to focus their attention on the most common changes and hopefully start addressing the question of how these may be slowed or stopped.

Dr Highley focused his talk mainly on the TDP-43 and SOD1 forms of inherited MND, with his colleague and fellow ‘Fellow’(!) Dr Johnathan Cooper-Knock, concentrating on the C9orf72 form (the most common cause of inherited MND). Through the MND Association’s DNA Bank  he has been able to obtain a large number of cell lines from patients with C9orf72 MND, along with detailed clinical information, which will allow him to compare patterns between those with fast progressing and those with more slowly progressing disease.

Although at a much earlier stage in his research, having started only 6 months ago, Dr Cooper-Knock has already identified some specific gene expression effects that may be distinct to the C9orf72 form of the disease. For more details about Dr Cooper-Knock’s work see our earlier blog post about his fellowship.

BioMOx and beyond

It was fitting that Dr Martin Turner (Oxford) gave the closing presentation. Not only was Dr Turner the first recipient of a Lady Edith Wolfson Fellowship, but he has recently been awarded a new five-year Senior Clinical Fellowship through the programme – these are highly prestigious awards, with only one in seven applicants successful.

Dr Martin Turner
Dr Martin Turner, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Titling his talk ‘BioMOx and beyond’ Dr Turner outlined the challenge of identifying a specific signature of MND. He showed that whilst there is unlikely to be a single test for MND, a combination of tests (involving brain scanning and eye tracking techniques together with chemical analysis of blood, urine or cerebrospinal fluid) are showing some promise in aiding and speeding up the diagnosis, as well as predicting how the disease is likely to progress within an individual.

He highlighted the importance of international collaboration, such as the new formal link with Dr Mike Benatar in Miami, who for several years has been studying people at risk of developing inherited MND. Indeed, Dr Turner apologised for missing the morning speakers at Sheffield as he had been busy with one of Dr Benatar’s study participants in his MRI scanner at Oxford!

On the subject of international collaboration, our most recent Clinical Fellow, Dr Jemeen Sreedharan, was unfortunately unable to attend as the first two years of his Fellowship is based at the University of Massachusetts, returning to the University of Cambridge to complete his research. We look forward to having him at the next Fellows get-together!