Failure Analysis of IBMPFD
Introduction
My educational background is in physics, while the majority of my career was in the
Quality and Reliability of Integrated Circuits. One of the prime activities was failure
analysis of circuits that had failed during manufacturing, in reliability stressing, or in
customer’s applications. There is a general standard of how to approach failure analysis
of integrated circuits. I am essentially applying the same methodology to understanding
more of IBMPFD (Inclusion Body Myopathy associated with Paget disease and
Frontotemporal Dementia).
An integrated circuit, even with billions of circuit elements, cannot perform the
complexity of functions as performed by biological cells. However, there are a number
of basic physical principals and similarities that are appropriate to compare when
considering the production processes for the circuits or cells. A failure in an integrated
circuit is the inability to comply with one or more specifications. For a biological cell,
for the purposes of this discussion, I am considering a failure of the cell (or some number
of cells) to perform one or more normal body functions.
The paradigm of failure analysis consists of identifying and clarifying various aspects of
the failure, including the failure mode, failure mechanism, failure cause, failure kinetics,
and then the subsequent corrective and preventive actions. Often this sequence of items
is nested, i.e., what is the failure cause at one level becomes the failure mode at a more
detailed level, e.g., as one proceeds from a packaged device to a circuit element to basic
atoms and molecules. Within an integrated circuit, one often has to get to the molecular
level to understand how or why a failure occurred.
A paradigm can also be applied to a disease (a failure of some body functions); the
symptoms are the mode, the mechanism is how the disease affects the body, the cause is
the genetic or environmental factor, the kinetics are how the genetic or environmental
factors determine the mechanism, the corrective action is a treatment, and the preventive
action is the cure.
One of the major problems with biological science, especially for the human body, is the
lack of complete knowledge (or complete theories) about how the body works, especially
the interactions of genetic and environmental components at the molecular level. The
following will attempt to put in non-medical jargon some concepts that may help some of
us understand what affects those of us with IBMPFD, as well as provide some direction
for future research.
General Description
IBMPFD encompasses a variety of autosomal dominant mutations in chromosome 9 that
affect the VCP (valosin containing protein or p97). This protein is used in a large
number of body functions, so most mutations are not viable, see paper
p97 and close encounters of every kind: a brief review
I. Dreveny1 , V.E. Pye1 , F. Beuron, L.C. Briggs, R.L. Isaacson, .J. Matthews, C.
McKeown, X. Yuan, X. Zhang and P.S.Freemont 2
Department of Biological Sciences, Centre for Structural Biology, Imperial College London, South
Kensington, London SW7 2AZ, U.K.
Some mutations are viable and result in adult onset of several symptoms, including
muscle atrophy, Paget disease of the bone, and frontotemporal dementia, see papers
Inclusion body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein
Giles D J Watts1, Jill Wymer1, Margaret J Kovach2, Sarju G Mehta1, Steven Mumm3,
Daniel Darvish4, Alan Pestronk5, Michael P Whyte3 & Virginia E Kimonis1
1Division of Genetics, Children’s Hospital Boston, 300 Longwood Avenue, Harvard Medical School,
Boston, Massachusetts 02115, USA. 2University of Tennessee at Chattanooga, Department of Biological
and Environmental Sciences, 215 Holt Hall-Department 2653, Chattanooga, Tennessee, USA. 3Division of
Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, and
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis,
Missouri, USA. 4HIBM Research Group, 16661 Ventura Boulevard, #311, Encino, California, USA.
5Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic
reticulum-associated degradation
Conrad C. Weihl1,2,*, Seema Dalal2, Alan Pestronk1 and Phyllis I. Hanson2
1Department of Neurology and 2Department of Cell Biology and Physiology, Washington University
School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
At this time, there is no known treatment or cure; however, the degree in variation of
onset and degradation among individuals with the identical mutation suggests that there
are other factors, both genetic and environmental, that could affect treatment and cure.
IBMPFD from a failure analyst point of view
Failure Mode: Although there are variations in what occurs, the following is a general
description. At some adult age there is weakness in various muscle groups, there may
also be at some age Paget disease of the bone and frontotemporal dementia. Eventually
muscle atrophy is complete, i.e., those muscle groups are no longer functional. Dementia
results in the loss of mental functions, e.g., memory, communication, and results in death.
The age of confirmation of symptoms and rate of degeneration vary by individual, even
siblings with the exact same mutation and a high degree of genomic similarity.
Failure Mechanism: The gradual accumulation of inclusion bodies (also called rimmed
vacuoles) in the affected muscle tissues appears to prevent normal muscle use as well as
tissue replacement. How the inclusion bodies initiate Paget disease is unknown. The
inclusion bodies also cause the dementia, similar to the plaque accumulation that causes
Alzheimer’s disease.
Failure Cause: A mutation in chromosome 9 affecting the VCP gene. In the case of the
R155 mutation, one base pair is changed, which changes one codon, which converts one
of the 40,000 or so amino acids that make up VCP. The mutated VCP then no longer
performs some of the expected functions.
Failure Kinetics: This area is not well understood at all. Possible items that could
explain how the mutation causes inclusion bodies include:
A.
A deficiency of VCP does not remove the inclusion bodies.
B.
The deformation in VCP creates the inclusion bodies or does not tag them
correctly so they are removed.
C.
The mutated VCP interacts with some other protein or enzyme to create or not
remove the inclusion bodies.
D.
Some combination of these items.
E.
Something else entirely.
This is an area where mouse studies (i.e., mice genetically engineered to have a mutation
in VCP) can help explain the kinetics.
Corrective Action: Obviously, not knowing the kinetics prevents any provable treatment
to work. This lack of knowledge should not prevent those of us with the mutation or
researchers from trying various things (see sections on nutrition and exercise at
www.ibmpfd.com and observing if something seems to help, even if not known why (in
theory or practice). Eventually treatments will not only recognize genetic variation, but
other variations between individuals that can affect how or how many inclusion bodies
are formed and removed, e.g., various bacteria in the gut, nutrition (particularly
supplements), exercise, and other variations in bodily system performance (metabolic,
blood, lymph, aerobic).
For example, knowing the composition and source of the inclusion bodies could suggest
the addition or removal of some proteins or amino acids to those affected. Depending on
what one adds or removes, one could use the blood system, digestive system, or other
means of addition or removal.
Preventive Action: A cure depends on being able to genetically re-engineer the human
body. Obviously, this approach will take a lot of time and a lot more knowledge than is
currently available, including how to correct the gene, how to deliver the correction, how
to prove nothing else is happening.
Prevention of future occurrences can happen if the affected parent knows of the mutation
(which is often not desirable because of medical insurance issues), then uses in vitro
fertilization and checks to blastocyte for the mutation. Implantation would only occur
with blastocytes (the first few cell divisions after egg and sperm join) that do not have
this mutation (a technique already used to prevent inheritance of other genetic diseases).
More failure analysis, looking at the first generation that has the mutation, i.e., neither
parent has the mutation. To me, there seems even less available knowledge in this area
than in the area previously discussed.
The next level of failure analysis considers the actual mutation as the failure mode.
Using the same methodology, one could analyze as follows:
Failure mode: As above for failure cause; A mutation in chromosome 9 affecting the
VCP gene. The mutated VCP then no longer performs some of the expected functions.
Failure mechanism: Somehow, when egg and sperm start initial cell division, the wrong
base pair is formed at the mutation location in chromosome 9. This mutation is then
copied at each subsequent cell division.
Failure cause: Mutations are naturally occurring events from a variety of sources, e.g.,
“folding errors”, cosmic rays. I am not sure an exhaustive list of sources exists and I do
not think the actual source of any given mutation can be determined. This is especially
true when the initial person with the mutation has died many years or generations ago.
Failure kinetics: Here there is even less knowledge about how the various possible
sources can “re-arrange” the elements that make up the base.
Corrective and preventive actions: These are mostly non-issues, since any work at the
DNA level requires significantly more knowledge and technology than currently exists.
To engineer at the DNA level would require both the mapping of the entire genome
quickly and accurately from a single cell from a blastocyte, as well as then being able to
correct any errors of the remaining cells of the blastocyte.
Conclusion
For those of us affected, the above summary intends to clarify some of the difficulties
facing researchers in determining a treatment and cure and provides some encouragement
for each affected individual to continue to experiment with various ideas to mitigate some
of the effects.
One of the things we can do to help research is to tabulate the symptoms and the time
when those symptoms were first noted. I intend to put a suggested form on the web site
that can be completed (anonymously if desired), and then the data can be analyzed.
For researchers, the above summary intends to provide a different perspective for
additional investigative and experimental approaches towards determining a treatment
and cure.