Correction- Mitochondrial Dysfunction & the Pathophysiology of ME/CFS

[Guest guest]

30 June I posted in Help ME Circle, the very

interesting article *Mitochondrial

Dysfunction & the Pathophysiology of

ME/cfs*.

Reference Co-Cure: http://bit.ly/MMvtyD

Yesterday I received the following message:

Dear Jan

As ever, you are nearly always first at

publicising new results. However, in this

case I would like you to issue a correction.

The problem is that IJCEM put my

manuscript on their website BEFORE

sending me the proof, and in the interim

between submission, review and

publication we authors made some

extensive changes and corrections

(including changing the title).

Today IJCEM have corrected this

situation, so please see their website for

the final version.

Best wishes, Norman

Norman E. Booth PhD FInstP

Emeritus Professorial Fellow in Physics,

Mansfield College, University of Oxford

Member, Clinic Group, Oxfordshire M.E.

Group for Action (OMEGA),

www.oxnet.org.uk/omega

Founder member, Advisory Group for NHS

Oxfordshire Community CFS/ME Team

(OCCMET)

Committee member, Oxfordshire

Neurological Alliance

Home address: 'Applegate', Orchard Lane

East Hendred, Wantage OX12 8JW, UK

tel. 01235 833486, e-mail:

norman.booth@...

````

So below you will find the *corrected* Abstract,

Introduction-, Discussion and Conclusions-sections,

and (for private members) an attachment in pdf

format of the *corrected* original version of:

Mitochondrial dysfunction and

the pathophysiology of Myalgic

Encephalomyelitis/Chronic

Fatigue Syndrome (ME/CFS)

which can also be found at: http://bit.ly/MI0DFS

Authors:

Norman E Booth1, Myhill2,

McLaren-3

Affiliation:

1Department of Physics and Mansfield College,

University of Oxford, Oxford UK; 2 Myhill Ltd,

Llangunllo, Powys UK; 3Acumen, Tiverton, Devon

UK

Journal:

Int J Clin Exp Med 2012;5(3):208-220 -

www.ijcem.com /ISSN:1940-5901/IJCEM1204005

Received April 26, 2012; accepted May 21, 2012;

Epub June 15, 2012; Published June 30, 2012

Address correspondence to: Dr. Norman E Booth,

PhD FInstP, Emeritus Professorial Fellow in

Physics, Mansfield College, University of Oxford,

UK E-mail: n.booth1@...

Abstract:

The objectives of this study are to test the

hypothesis that the fatigue and accompanying

symptoms of Chronic Myalgic Encephalomyelitis/

Fatigue Syndrome are in part due to defects in

energy provision at the cellular level, and to

understand the pathophysiology of the defects so

that effective medical intervention can be

implemented.

We performed an audit of 138 patients (ages 18-65)

diagnosed with ME/CFS and attending a private

practice.

The patients and 53 normal, healthy controls had

the ATP Profile test carried out on neutrophils from

a 3-ml venous blood sample.

This test yields 6 numerical factors that describe

the availability of ATP and the efficiency of

oxidative phosphorylation in mitochondria.

Other biomedical measurements, including the

concentration of cell-free DNA in plasma, were

made.

The results of the audit are compared with the

controls and a previous cohort of 61 patients.

We find that all patients tested have measureable

mitochondrial dysfunction which correlates with the

severity of the illness.

The patients divide into two main groups

differentiated by how cellular metabolism attempts

to compensate for the dysfunction.

Comparisons with exercise studies suggest that the

dysfunction in neutrophils also occurs in other

cells. This is confirmed by the cell-free DNA

measurements which indicate levels of tissue

damage up to 3.5 times the normal reference

range.

The major immediate causes of the dysfunction are

lack of essential substrates and partial blocking of

the translocator protein sites in mitochondria.

The ATP Profile is a valuable diagnostic tool for the

clinical management of ME/CFS.

Introduction

The devastating illness Myalgic Encephalomyelitis

(M.E.) also called Chronic Fatigue Syndrome

(CFS) is often misunderstood and considered to

be *all in the mind*.

E. D. Acheson (later to become

Chief Medical Officer of England) and others

carefully described the symptom pattern of

Myalgic Encephalomyelitis as long ago as 1959

[1], and the World Health Organization recognized

M.E. as a neurological illness in 1969.

However these facts are ignored by a substantial

fraction of the medical community, and a

patient can be labeled as having ME/CFS or just

M.E. by just being chronically fatigued.

The most characteristic and disabling symptom of

M.E. is the postexertional malaise following activity

or exercise, either physical or mental, often one to

three days later.

Fortunately, the importance of this key symptom

has been recognized in recent years and

incorporated into the International Consensus

Criteria for Myalgic Encephalomyelitis (ICCME) [2].

In spite of many biomedical studies, there is

inadequate understanding of the biochemical

processes which lead to this malaise and there is

no recognized biomedical test for this illness.

In the first Section, we demonstrate that

biochemical tests such as the ATP Profile do exist

that can identify those patients who have a cellular

biological reason for their symptoms.

In the second Section, we use the results of the

various tests which make up the ATP Profile to

unravel the basic pathophysiology of the

mitochondrial dysfunction and how cellular

processes are modified in an attempt to compen-

sate for the dysfunction. We also report on the

measurement of DNA fragments in blood

plasma (cell-free DNA), produced as a result of

cell damage in ME/CFS.

Discussion and conclusions

Diagnosis of ME/CFS

The ATP profile is a test which provides numerical

values of 6 biomedical quantities regarding

energy provision by the mitochondria in neutrophils,

the main effectors of the innate immune

system.

The ATP Profile is an objective test of ME/CFS and

clearly shows that this illness has a physical basis.

Individually and collectively the biomedical

quantities select patients whose symptoms are the

direct result of mitochondrial dysfunction.

These quantities also reflect the severity of the

illness and, together with one or more additional

tests such as Cell-free DNA they demonstrate that

it is not just neutrophils that are dysfunctional but

also other biological systems.

In some cases there may be a co-morbid

psychiatric disorder but it hardly seems necessary

to perform a psychiatric diagnosis as a matter of

course, as has been proposed [30]. Many

accompanying mental symptoms can be explained

as resulting from the long period of physical

disability endured by many sufferers.

Pathophysiology of ME/CFS

Our results clearly show mitochondrial dysfunction

in all 138 patients of Cohort 2 and also the 61

patients of Cohort 1 [3].

A major factor in the dysfunction is partial blocking

of the translocator protein TL, and this has not

been investigated in any other study of ME/CFS or

in most other studies of illnesses with mitochondrial

dysfunctions of various types [9].

We also find that lack of substrate or essential

co-factors contributes to the mitochondrial

dysfunction of some patients, particularly those

with super-normal values of TL IN (sub-group

A2).

Another feature that we have uncovered is that

there are at least two alternative processes that

cells and their mitochondria use in order to partially

compensate for the dysfunction.

This division into 2 distinct groups, A and B,

appears to correlate with the 2 groups observed in

some exercise studies [21, 23].

Future exercise studies coupled with tests like the

ATP Profile are needed to confirm this correlation.

Our measurements of Cell-free DNA show that

ME/CFS patients have abnormally high levels of

damaged and necrotic cells and that there is

strong correlation with the measured mitochondrial

dysfunction.

Taken together, these measurements show that

ME/CFS is a serious illness which may affect

every cell in the body.

Implications for the treatment of ME/CFS

Here we have emphasized the use of biomedical

tests to aid in the diagnosis and to vastly improve

our knowledge of the pathophysiology involved in

this illness.

In addition, these biomedical tests can act as a

valuable guide for medical and therapeutic

interventions. These will be discussed in a paper

which is in preparation.