Format

Send to

Choose Destination
Ann Neurol. 2018 Apr;83(4):756-770. doi: 10.1002/ana.25198. Epub 2018 Mar 30.

Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination.

Author information

1
Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.
2
Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN.
3
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN.
4
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN.
5
Department of Neurology, Stanford University, Palo Alto, CA.
6
Department of Neurology, University of Iowa, Iowa City, IA.
7
Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH.
8
Department of Laboratory Medicine, Second Affiliated Hospital of Qingdao University, Qingdao, China.
9
Tennessee Valley Healthcare System-Nashville VA, Nashville, TN.

Abstract

OBJECTIVE:

Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J.

METHODS:

Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological, and biochemical approaches.

RESULTS:

We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with nonuniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/- ). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve-blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+ . Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination.

INTERPRETATION:

Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+ . Injection of a Ca2+ chelator into Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770.

PMID:
29518270
PMCID:
PMC5912982
[Available on 2019-04-01]
DOI:
10.1002/ana.25198

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center