Dysmyelination and Demyelination: Revisited

A few years ago I wrote quite a long post about the differences between demyelination and dymyelination, and it involved a great deal of speculation on my part. The general gist was that I thought that in CMT1a dysmyelination was likely to be the biggest factor, with demyelination occuring in a age-length dependent fashion, whereas HNPP would be mostly demyelination caused by the repetitive episodes of nerve injury, and less likely to be affected by inherent dysmyelination, which thinking about it is probably wrong, because of the inherent fragility of the myelin caused by low pmp22 dosage effects.

I suppose I ought to define the terms, dysmyelinating, and demyelinating. My rather cod-definition goes as follows,

Dysmyelination – myelin that is Dysfunctional from the outset, ie formed incorrectly and may not function optimally.

Demyelination – Myelin which is damaged or diseased and breaks down and becomes non-functional, it may have been fully functional before the ‘demyelinating’ event.

HNPP and CMT1a are therefore both Dysmyelinating and Demyelinating.


I did see a study a few months ago which suggested that dysmyelination was just as prominent in HNPP as CMT1a, and that many of the conduction block and episodes of pressure palsy could be accounted for by inherent conduction abnormality of pmp22 deficient nerves rather than segmental demyelination.

Today as I was scanning pubmed for new studies, I saw a suggested search term that I hadn’t used before, which resulted in quite a few different studies.

PMP22 (HNPP) gene function

First in the list (18/8/2014) is

Abnormal junctions and permeability of myelin in PMP22-deficient nerves

1. Ann Neurol. 2014 Feb;75(2):255-65. doi: 10.1002/ana.24086. Epub 2014 Feb 20.

Abnormal junctions and permeability of myelin in PMP22-deficient nerves.

Guo J(1), Wang L, Zhang Y, Wu J, Arpag S, Hu B, Imhof BA, Tian X, Carter BD,
Suter U, Li J.

Author information:
(1)Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain
Institute, Vanderbilt University School of Medicine, Nashville, TN.

OBJECTIVE: The peripheral myelin protein-22 (PMP22) gene is associated with the
most common types of inherited neuropathies, including hereditary neuropathy with
liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the
function of PMP22 has yet to be defined. Our previous study has shown that PMP22
deficiency causes an impaired propagation of nerve action potentials in the
absence of demyelination. In the present study, we tested an alternative
mechanism relating to myelin permeability.
METHODS: Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin
junctions and their permeability using morphological, electrophysiological, and
biochemical approaches.
RESULTS: We show disruption of multiple types of cell junction complexes in
peripheral nerve, resulting in increased permeability of myelin and impaired
action potential propagation. We further demonstrate that PMP22 interacts with
immunoglobulin domain-containing proteins known to regulate tight/adherens
junctions and/or transmembrane adhesions, including junctional adhesion
molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or
Mag in mice recapitulates pathology in HNPP.
INTERPRETATION: Our study reveals a novel mechanism by which PMP22 deficiency
affects nerve conduction not through removal of myelin, but through disruption of
myelin junctions.

© 2014 American Neurological Association.

PMID: 24339129 [PubMed – indexed for MEDLINE]


Much of this flies above my head, but the conclusion that abnormal nerve impulse propagation occurs regardless of whether demyelination has occured or not, suggests that Dysmyelination is very much significant in HNPP, ie inherently slowish nerve conduction velocities, independent of any active sites of demyelination.

Maybe that’s just obvious, as all people with HNPP show slower than normal conduction velocities, regardless of whether or not they are symptomatic or not.

But it’s progress…


2 thoughts on “Dysmyelination and Demyelination: Revisited

  1. Jon.. this is interesting, since up to now, it has been thought to be the ‘demylination’ process involved in HNPP causing the issues with. and this..

    INTERPRETATION: Our study reveals a novel mechanism by which PMP22 deficiency
    affects nerve conduction not through removal of myelin, but through disruption of
    myelin junctions.

    This kind of changes he whole ballgame and into which direction the research needs to go..

    • I agree Tommy, it should provide many more choices for potential drugs which could improve nerve conduction, and if they can also improve myelin strength, then we’d be looking at potential ‘cures’. A few years down the line though.

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