Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment

Abstract

Neurofibromatosis type 1 (NF1) is the most common of a group of rare diseases known by the term, "Neurofibromatosis," affecting 1 in 3000 to 4000 people. NF1 patients present with, among other disease complications, café au lait patches, skin fold freckling, Lisch nodules, orthopedic complications, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, cognitive impairment, and chronic pain. Although NF1 patients inevitably express pain as a debilitating symptom of the disease, not much is known about its manifestation in the NF1 disease, with most current information coming from sporadic case reports. Although these reports indicate the existence of pain, the molecular signaling underlying this symptom remains underexplored, and thus, we include a synopsis of the literature surrounding NF1 pain studies in 3 animal models: mouse, rat, and miniswine. We also highlight unexplored areas of NF1 pain research. As therapy for NF1 pain remains in various clinical and preclinical stages, we present current treatments available for patients and highlight the importance of future therapeutic development. Equally important, NF1 pain is accompanied by psychological complications in comorbidities with sleep, gastrointestinal complications, and overall quality of life, lending to the importance of investigation into this understudied phenomenon of NF1. In this review, we dissect the presence of pain in NF1 in terms of psychological implication, anatomical presence, and discuss mechanisms underlying the onset and potentiation of NF1 pain to evaluate current therapies and propose implications for treatment of this severely understudied, but prevalent symptom of this rare disease.

Figure 1.. Anatomical indication of reported NF1 pain.

(A) Table showing body regions indicated in NF1 case reports as having NF1-related pain. (B) Human model representing anatomy of implicated in NF1 pain reports. Red color represents anterior regions; orange color represents posterior regions.

Figure 2.. Convergent signaling involving CRMP2 and Neurofibromin controls CaV2.2 and NaV1.7 activity and NF1-related pain.

Our previous work identified a direct binding between CaV2.2 and CRMP2 leading to a CRMP2-mediated increase in Ca²⁺ current density and increased CGRP release in sensory neurons [11; 12]. Loss of CRMP2/neurofibromin interaction increases CRMP2 phosphorylation and binding to CaV2.2 and NaV1.7 [77; 83].