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Focal Deficits In Myelination In Human Neuroma-in-Continuity
Fred De Winter, PhD1; Arie C Van Vliet, Msc1; Martijn R Tannemaat, PhD, MD2; Sjoerd G Van Duinen, PhD, MD2; Martijn J.A. Malessy, MD; PhD2; Joost Verhaagen, PhD1
1Netherlands Institute for Neuroscience, Amsterdam, Netherlands, 2Leiden University Medical Center, Leiden, Netherlands
In 10% of the patients with neonatal brachial plexus palsy (NBPP) a neuroma-in-continuity (NIC) is formed that is thought to interfere with axonal outgrowth and prohibits functional recovery. However, the biological mechanisms underlying this problem are currently poorly understood. To increase our knowledge of NIC we initiated a characterization of NIC tissue resected during reconstructive surgery. In a microarray study we revealed that 722 genes are differentially regulated between the NIC and the proximal nerve. We observed that in the NIC, when compared to the proximal nerve stump, there is a decrease Schwann cell and myelin related gene expression in favor of more fibroblast and fibrosis related gene expression.
To examine the possible implication of a reduced Schwann cell/myelin profile we performed a systematic analysis of large series of NIC tissue (17 NBPP, 3 adult traumatic brachial plexus lesion) by immunohistochemistry. This revealed that in 74% of the patients, the NIC contains multiple focal myelin deficits (FMDs). These FMDs contain Schwann cells that enwrap axons but do not form myelin. Axons in the FMDs have disrupted nodes of Ranvier with decreased expression Caspr and Ankyrin, and reduced Na(v)1.6 channel clustering. Based on the number, shape and size of the FMDs we calculated that there is a ~95% change that an axon in a NIC will encounter 10 FMDs. Therefore FMDs may be a part of the pathobiologic basis for the absence of functional recovery in NBPP. These observations provide a basis for the development of novel strategies to promote functional recovery after neonatal plexus palsy by improving myelination in the NIC.
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