From DNA to drug development. Five success stories show the potential of DecodeME

Posted on 05/09/2021 by wames

DecodeME Study blog: From DNA to drug development. Five success stories show the potential of DecodeME

 

How do you find treatments for a disease like ME/CFS, where nothing is known for sure about its causes?

One way scientists can now look for answers is with very large DNA studies, like DecodeME. This fairly new approach is already giving insights and pointing to treatments for a range of illnesses, including rheumatoid arthritis, type II diabetes and even severe Covid.

The clue lies in our DNA

DecodeME will use small differences in the DNA of people with ME/CFS to look for biological causes of the disease.

DecodeME will use small differences in the DNA of people with ME/CFS to look for biological causes of the disease.

Tiny differences in our DNA can help pinpoint what’s going wrong in our bodies. And understanding what’s going wrong biologically is the starting point for finding treatments.

DNA is the master molecule of life, storing all the information needed to make and run the human body. The information is stored in DNA using chemical letters. There are only four letters, but our DNA contains a sequence of 3 billion of them, like a very long book.

Mostly, our sequence of letters is exactly the same as those of the next person. But for around a million positions in the book (fewer than one in every one thousand), the letter can differ from person to person.

Scientists then compare these DNA letter differences between people with an illness, such as ME/CFS, and healthy people. Often, they find that a few of these differences are slightly more common in people with a particular disease than those without it.

These DNA differences, perhaps only a dozen or two, are clues to what is going wrong in an illness.

Here are five examples where the differences found by big DNA studies have helped scientists to understand the biological causes of an illness and to develop treatments.

Summary: 5 big DNA study successes

Big DNA studies are still relatively new and the science that drives them is developing all the time. But these five examples show the power of the approach.

  1. In rheumatoid arthritis, it led to ongoing development of new drugs that aim to tackle the root of the problem.
  2. It led to the discovery that several autoimmune diseases could be treated with drugs already developed for other diseases.
  3. In Type II diabetes, a surprising discovery led to development work on a new drug.
  4. In Alzheimer’s disease, DNA research indicated that researchers should look for answers in the brain’s “support cast” of cells.
  5. And in Covid-19, the most devastating illness to strike the world in over 100 years, a DNA study has already provided powerful clues to scientists looking for life-saving drugs.

Looking for answers across human biology

One of the main advantages of big DNA studies is that they look across all 3 billion letters that make up the DNA book of life. This means that they are effectively scanning the whole of human biology.

Read more 

This is particularly important for a disease like ME/CFS where we know so little – you don’t even need to know what you’re looking for.

There are no guarantees with any research study, but we hope that DecodeME will make a big difference.

First, we need to find 20,000 people to take part. If you would like to be one of them, please sign up and you can be first in line when we start recruiting in the autumn.

Sign up

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ME/CFS: whole genome sequencing uncovers a misclassified case of glycogen storage disease type 13 previously diagnosed as ME/CFS

Posted on 05/07/2021 by wames

ME/CFS: whole genome sequencing uncovers a misclassified case of glycogen storage disease type 13 previously diagnosed as ME/CFS, by Donna Brown, Camille Birch, Jarred Younger, Elizabeth Worthey in Molecular Genetics and Metabolism Vol 132, Supp 1, April 2021, Pages S194-S195

 

Article extract:

Currently, there exists at least 2 widely used diagnostic standards; the Canadian (Carruthers, 2011) and the CDC 1994 criteria (Fukuda, 2004) for ME/CFS. The variety of diagnostic criteria result in a range of estimates of prevalence; most recently using the CDC-1994 criteria and meta-analysis the prevalence was assessed at 0.89% (Lim, 2020). Even with these standards in place, current patients can be misdiagnosed.

Glycogen Storage Disease

Hypothesizing that ME/CFS is the result of an intrinsic genetic defect (s) and each patient is best considered individually, we performed whole genome sequencing (WGS) combined with informatics approaches to identify molecular variants of interest in a pilot cohort of ME/CFS patients. Among this pilot we identified a patient harboring a likely pathogenic ENO3 variant. Other variants in ENO3, the betaenolase gene, are identified to be affected in patients with glycogen storage disease type 13 (GSD13), a rare autosomal recessive adult onset disorder.

Symptoms of GSD13 include exercise intolerance and muscle pains and it is thought to present with symptoms milder than other glycogen storage diseases. This patient reports feeling pain, spasms, and heaviness in her limbs (especially her legs), restricting her physical activity to once or twice a week, and has problems with concentration and other complaints typical of a subset of ME/CFS patients.

It has been estimated that between 836,000 and 2.5 million Americans suffer from ME/CFS and yet little is known about the molecular underpinnings of disease. Clearly, the time has come to consider genomic sequencing as part of the standard of care to diagnose and classify these patients.

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Recovery from paediatric CFS – definitions are highly variable

Posted on 05/06/2021 by wames

Recovery from chronic fatigue syndrome: a systematic review-heterogeneity of definition limits study comparison, by Yasmin Moore, Teona Serafimova, Nina Anderson, Hayley King, Alison Richards, Amberly Brigden, Parisa Sinai, Julian Higgins, Caitlin Ascough, Philippa Clery, Esther M Crawley in Arch Dis Child. 2021 Apr 12 [DOI: 10.1136/archdischild-2020-320196]

 

Review abstract: 

Background:

Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common illness with a major impact on quality of life. Recovery is poorly understood. Our aim was to describe definitions of recovery in paediatric CFS/ME, the rate of recovery and the time to recovery.

Methods:

This systematic review included a detailed search of MEDLINE, EMBASE, PsycInfo and Cochrane Library between 1994 and July 2018. Inclusion criteria were (1) clinical trials and observational studies, (2) participants aged <19 years with CFS/ME, (3) conducted in Western Healthcare systems and (4) studies including a measure of recovery and time taken to recover.

Results:

Twelve papers (10 studies) were identified, involving 826 patients (range 23-135). Recovery rates were highly varied, ranging between 4.5% and 83%. Eleven distinct definitions of recovery were used; six were composite outcomes while five used unidimensional outcomes. Outcome measures used to define recovery were highly heterogeneous. School attendance (n=8), fatigue (n=6) and physical functioning (n=4) were the most common outcomes included in definition of recovery. Only five definitions included a personal measure of recovery.

Implications:

Definitions of recovery are highly variable, likely secondary to differences in study design, outcomes used, follow-up and study populations. Heterogeneous definitions of recovery limit meaningful comparison between studies, highlighting the need for a consensus definition going forward. Recovery is probably best defined from the child’s own perspective with a single self-reported measure.

If composite measures are used for research, there should be agreement on the core outcome set used.

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Long COVID & ME/CFS – a systemic review & comparison of clinical presentation & symptomatology

Posted on 05/05/2021 by wames

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a systemic review and comparison of clinical presentation and symptomatology, by Timothy L Wong, Danielle J Weitzer in Medicina 2021, 57(5), 418; [doi.org/10.3390/medicina57050418]

 

Review abstract:

Background and Objectives:

Long COVID defines a series of chronic symptoms that patients may experience after resolution of acute COVID-19. Early reports from studies with patients with long COVID suggests a constellation of symptoms with similarities to another chronic medical illness-myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

A review study comparing and contrasting ME/CFS with reported symptoms of long COVID may yield mutualistic insight into the characterization and management of both conditions.

Materials and Methods:

A systemic literature search was conducted in MEDLINE and PsycInfo through to 31 January 2021 for studies related to long COVID symptomatology. The literature search was conducted in accordance with PRISMA methodology.

Results:

Twenty-one studies were included in the qualitative analysis. Long COVID symptoms reported by the included studies were compared to a list of ME/CFS symptoms compiled from multiple case definitions. Twenty-five out of 29 known ME/CFS symptoms were reported by at least one selected long COVID study.

Conclusions:

Early studies into long COVID symptomatology suggest many overlaps with clinical presentation of ME/CFS. The need for monitoring and treatment for patients post-COVID is evident. Advancements and standardization of long COVID research methodologies would improve the quality of future research, and may allow further investigations into the similarities and differences between long COVID and ME/CFS.

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Development of an inertial measurement-based assessment of disease severity in CFS

Posted on 05/05/2021 by wames

Development of an inertial measurement-based assessment of disease severity in Chronic Fatigue Syndrome, by Turner Palombo, Suzanne Vernon, Shad Roundy in Digital Commons (Utah Space Grant Consortium grant) 2020 Paper 11. Published May 2021

 

Research abstract: 

While myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is relatively new and poorly understood, a recent upsurge in research has identified the disease’s core symptoms, including post-exertional malaise and orthostatic intolerance. The FDA has yet to approve any treatments for ME/CFS, partially due to a lack of validated efficacy
endpoints.

The central focus of this research is to develop ME/CFS efficacy endpoints using a non-invasive, inertial measurement-based approach. Accessible endpoints will provide a way to properly evaluate potential treatments for ME/CFS. Using a Kalman filter, inertial measurement unit (IMU) data can be converted to optimized leg angle estimates. These
angle estimates can then be converted to personalized daily measurements of upright activity, referred to as uptime.

In a six-day, case-control study conducted by the Bateman Horne Center, uptime was measured for 15 subjects (five controls, five moderate-level ME/CFS, and five severe-level ME/CFS).  Analysis of these uptime scores indicated that each group spends different proportions of their days upright and active. This result shows that uptime can accurately
determine disease severity and is, therefore, a reliable endpoint for evaluating ME/CFS treatment efficacy.

Conclusion

This research proves the value of uptime as an objective replacement for HUA. Analysis of collected uptime data indicates that disease groups spend different proportions of the
day upright and active. Healthy individuals are expected to have weekly uptime scores above 30%, subjects with moderate ME/CFS are expected to have weekly uptime scores between 20% and 30%, and subjects with severe ME/CFS are expected to have weekly uptime scores below 20%.

Another objective of our study was to evaluate the effects of PEM brought on by the NASA Lean Test. Our results showed no change in uptime after the NASA Lean Test. Although this contradicts our expectations, we have confirmed that this test is humane; patients with ME/CFS do what they can to avoid stress-causing exertion, but we have seen that this test does not cause a drastic decrease in uptime—indicating that they aren’t significantly hurt by the test. Future studies should incorporate home-visits to reduce the stress caused by participation, thereby ensuring that PEM is only induced by researchers during the
Lean Test.

Accurate uptime measurements will become invaluable for healthcare providers in assisting ME/CFS patients. Furthermore, uptime provides a method for pharmaceutical companies and independent researchers to prove the efficacy of their treatments—a critical step towards receiving FDA-approval. The BHC’s data shows that patients with severe ME/CFS are limited to a bed or reclining chair for all but five hours each day; increasing this number would be life-changing.

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Case report: angina simultaneously diagnosed with the recurrence of ME/CFS

Posted on 05/04/2021 by wames

Angina simultaneously diagnosed with the recurrence of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Koki Li, Yuki Otsuka, Yasuhiro Nakano, Daisuke Omura, Kou Hasegawa, Mikako Obika, Keigo Ueda, Hitomi Kataoka and Fumio Otsuka in Diagnostics Vol 11 no. 3 [10.3390/diagnostics11030460] 6 March 2021

 

Case report abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) mainly affects young adults and can have a potential impact on social functioning. As this syndrome is associated with endothelial dysfunction, the heart can be damaged via ischemia due to endothelial damage. This might potentially lead to heart failure, which accounts for approximately 20% of deaths among patients with ME/CFS.

While cardiac ischemia is thought be a pathophysiologically important manifestation of this syndrome, this is not yet reported. Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker.

We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.

Excerpt from discussion

In conclusion, we experienced an interesting case in which vasospastic or microvascular angina was detected along with concurrent exacerbation of ME/CFS severity. This suggested that cardiac manifestations can appear as a result of deterioration. As the symptoms experienced by patients with ME/CFS might mimic those of angina, diagnosis of the latter might be easily missed. Thus, it is pertinent that cardiac examinations be conducted in such patients to rule out the possibility of heart ischemia.

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ME Awareness raising in Wales 2021

Posted on 05/03/2021 by wames

ME Awareness in Wales 2021

 

Awareness raising can happen at any time, by anyone, but traditionally the ME community individually and in groups have focussed efforts around 2 dates in the year:

blue ribbon photoInternational ME Awareness Day – 12 May

Severe ME Awareness Day – 8 August

WAMES has plans this year to spread the word about ME in both May and August. Read on to find about how and why, and how you can join in.

 

Why raise awareness?

We feel the need to raise awareness because ME has been misunderstood, stigmatised and even  ignored by those who should be helping and supporting us ever since a viral outbreak in the Royal Free Hospital in London 65 years ago led to staff and patients developing the long term health condition that was studied and given the name ‘Myalgic encephalomyelitis’ by Dr Melvin Ramsay.

How has WAMES raised awareness?

WAMES has been speaking out about the need for better health and social care for people with ME in Wales since devolution, over 20 years ago.

More recently, in 2018 WAMES went to the Senedd seeking help for “a health and social care crisis – a humanitarian crisis“. Politicians listened and expressed sympathy but the NHS appeared unmoved.

In 2019 we highlighted that ME is a global health scandal, not just an issue in Wales, that people with ME are not asking for special treatment. We are asking for humane treatment and health equality. Again, we were met with silence.

In 2020 the pandemic hit and many people were affected by a global health crisis. We recognised similarities between many long people affected by long COVID and ME, and knew that this virus could trigger long term ME in some and increase our numbers significantly. We asked the Welsh Government for a combined health and care strategy for all post viral illnesses. This was ignored and it was announced that no new services would be developed for long COVID and (like ME is supposed to be) they would be treated through existing health services.

This year?

It is now 2021. Has anything changed? Have we any reason to believe that we will be heard and heeded this year? There are 2 hopeful signs.

We believe there is a growing understanding of post viral illness in all sectors of society, due to the increasing numbers of people struggling with long COVID. We also have reason to hope that the revised NICE guideline, which will be published in August, will make it easier for health professionals to understand and care for us.

May 2021 – ME facts and quotes

This month we will be spreading key facts about ME through our social media and online platforms. We are asking researchers and professionals in Wales who have an interest in ME (yes there are some!) to give us quotes about ME from their own experience.

  • Send us your favourite facts and quotes, as short and snappy as possible
  • Do you know a professional who has something helpful to share about ME?

August 2021 – ME health and care needs

In July we will launch a survey to find out what help patients and carers really need so we can present this to Health Boards,  GP groups and Social Services in August. At the same time we will be highlighting the key messages  of the newly published NICE guideline for ME/CFS via social media and directly with all those who need to know.

In the meantime if you are holding your own awareness raising events, please let us know so we can advertise and celebrate with you. Let’s join together to raise our voices for ME  in Wales!

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‘Having severe ME/CFS is so close to being dead’: extremely severe ME/CFS – a personal account’

Posted on 04/30/2021 by wames

Extremely severe ME/CFS — A personal account, by Whitney Dafoe in Healthcare Vol 9, #5, p 504, April 27, 2021 [doi.org/10.3390/healthcare9050504]

 

Article abstract:

Whitney Dafoe before ME

A personal account from an Extremely Severe Bedridden ME/CFS patient about the experience of living with extremely severe ME/CFS. Illness progression, medical history, description of various aspects of extremely severe ME/CFS and various essays on specific experiences are included.

7.2. The Great Beyond (conclusion to article)

Having Severe ME/CFS is so close to being dead. There’s really no other way to describe the experience I have had. I don’t think it’s something that people who haven’t had severe ME/CFS can likely understand. Looking back at who I was when I had mild and moderate ME/CFS, I’m not sure it’s something that even patients who haven’t been in the extremely severe state can fully understand. I was literally barely alive, and I am confident that, in a short time, science will prove that severe ME/CFS patients are barely alive and that ME/CFS patients, in general, are less alive mentally and physically than healthy people.

I think the only time a healthy person maybe experiences anything like this is shortly before actually dying. In that case, the person is generally in this state for a much shorter period of time and so remains much more connected to who they were, and their former lives. This is the state in which healthy people let go of their former lives and accept death, which is probably one of the reasons that suicide is so common for ME/CFS patients.

When I was severely ill, I lost so much of myself. I was holding on to fragmented memories left imprinted in my mind of who I was, but that person, in reality, didn’t exist anymore. The thought patterns and emotions and worldviews that created the person I was no longer existed. However, I was still technically alive, just enough to be conscious and bear witness to this state of non-existence.

The suffering this causes is so profound. I can only liken it to one of the hell realms described in Tibetan Buddhism. A world full of nothing but pain, loss, agony and constant never-ending challenges in holding on to what little I had left. Every mistake took me deeper into the void of nothingness.

As you know, I have recently gained back some of my mind and body. It feels like coming back from the dead. I’m in a strange state now, where bits and pieces of Whitney have come back to life but most of me has not. I’m not able to get out of bed, eat or drink water or go out and feel the world again—feel that feeling that is being alive.

I have, so far, just been riding this wave of improvement and the new-found abilities I have, like being able to write and have some semblance of connection with the world again.

However, the honeymoon phase for these improvements wore off, I started realizing how far I actually am from being Whitney again. I’ve realized that I don’t really know who I am anymore. I know who I used to be, but is that who I am? I guess I’ve realized that it is not.
The experience of being on death’s door for never-ending years has changed me permanently. I’m still not well enough to come anywhere close to fully inhabiting my own mind and body again. I don’t really know who I am. I’m in a sort of limbo right now, stripped of the person I once was and would have become, but not able to take the experiences I’ve had and create a new person out of them. I’m still a ghost, suddenly no longer fully transparent, yet, at the same time, unable to actually exist in physical form.
It’s so confusing.

While my new capabilities have improved my quality of life a small amount, I realize how much I’m still suffering and how much is still missing from my being a human being again. I’ve been so focused on my small improvements that I’ve somewhat lost touch with how far away the world still is. When I think about it now, it’s hard for me to even imagine what it would be like to be fully healthy again, out in the world again, alive again.

I don’t know who I am going to become. One thing I do know is how much the experience of losing everything has taught me. I think ME/CFS is the greatest teacher I’ve ever had. I have hope that when better treatments, and then a cure, are found, I will be a much more conscious, wiser, more realized being. That person waiting to be reborn is an incredible person, and I can’t wait to see that person and be that person and contribute to the world with my whole being (see Appendix A.9).

I think this is one of the most tragic things about the high rate of suicide among ME/CFS patients. These are people who have been through something completely unique to the rest of society and have a truly unique and profound perspective to offer the human race. When an ME/CFS patient kills themselves, so much is lost from the world.

We have seen the other side. We need to stay alive so that we can join the world again and share what is really out there in the great beyond with the rest of humanity. We have an incredible understanding of what life is. How precious and fleeting it is, how little time we have, and more. These are lessons that most people never learn, and we need to teach the rest of humanity how sacred the life they have truly is.

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The role of prevention in reducing the economic impact of ME/CFS in Europe: a report from EUROMENE

Posted on 04/29/2021 by wames

The Role of Prevention in Reducing the Economic Impact of ME/CFS in Europe: A Report from the Socioeconomics Working Group of the European Network on ME/CFS (EUROMENE) by  Derek F H Pheby, Diana Araja, Uldis Berkis, Elenka Brenna, John Cullinan, Jean-Dominique de Korwin, Lara Gitto, Dyfrig A Hughes, Rachael M Hunter, Dominic Trepel and Xia Wang-Steverding in Medicina 2021, 57(4), 388;  [doi.org/10.3390/medicina57040388]

 

Report abstract:

This report addresses the extent to which there may be scope for preventive programmes for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and, if so, what economic benefits may accrue from the implementation of such programmes. We consider the economic case for prevention programmes, whether there is scope for preventive programmes for ME/CFS, and what are the health and economic benefits to be derived from the implementation of such programmes.

We conclude that there is little scope for primary prevention programmes, given that ME/CFS is attributable to a combination of host and environmental risk factors, with host factors appearing to be most prominent, and that there are few identified modifiable risk factors that could be the focus of such programmes. The exception is in the use of agricultural chemicals, particularly organophosphates, where there is scope for intervention, and where Europe-wide programmes of health education to encourage safe use would be beneficial.

There is a need for more research on risk factors for ME/CFS to establish a basis for the development of primary prevention programmes, particularly in respect of occupational risk factors. Secondary prevention offers the greatest scope for intervention, to minimise diagnostic delays associated with prolonged illness, increased severity, and increased costs.

Read about the EUROMENE Socio-economic working group

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Pathophysiology of skeletal muscle disturbances in ME/CFS

Posted on 04/27/2021 by wames

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), by Klaus J Wirth & Carmen Scheibenbogen in Journal of Translational Medicine vol 19, no. 162 (2021) [doi.org/10.1186/s12967-021-02833-2]

 

Review abstract:

Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS.

Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis).

Key symptoms of ME/CFS related to hypoperfusion

An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms.

In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis.

The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia–reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification.

Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle.

Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

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