Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Mar;12(2):e200368.
doi: 10.1212/NXI.0000000000200368. Epub 2025 Jan 17.

Clinical Manifestations and Treatment Responses in Pediatric Neurofascin 155-IgG4 Autoimmune Nodopathy

Hebatallah R Rashed  1   2 , Naveen Kumar Paramasivan  1 , Duygu Selcen  1 , P James B Dyck  1 , Smathorn Thakolwiboon  1 , Michelle L Mauermann  1 , John Mills  3 , Divyanshu Dubey  1   3
Affiliations

Clinical Manifestations and Treatment Responses in Pediatric Neurofascin 155-IgG4 Autoimmune Nodopathy

Hebatallah R Rashed et al. Neurol Neuroimmunol Neuroinflamm. 2025 Mar.

Abstract

Background and objectives: While it is well characterized in adults, little is known about the clinical features of neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN) in the pediatric population. In this study, we aimed to describe the clinical features and treatment outcomes in children diagnosed with neurofascin 155-IgG4 autoimmune nodopathy (NF155-IgG4 AN).

Methods: Pediatric and adult patients with NF155-IgG4 AN were identified retrospectively through the Mayo Clinic Neuroimmunology Laboratory database.

Results: Eight pediatric and 20 adult patients with NF155-IgG4 AN were included with a median age at onset of 11 and 43 years, respectively. Pediatric patients (3/8) were often diagnosed initially with Guillain-Barre syndrome compared with adults (2/20) (p = 0.123). Six pediatric patients deteriorated beyond 2 months with rapid progression to disease nadir compared with adults (22 vs 52 weeks, p = 0.04). All had distal predominant weakness with paresthesias. Four patients had tremor, and one had cerebellar ataxia. Sensory ataxia was significantly less common in pediatric patients (4/8) compared with adults (18/20) (p = 0.038). Most pediatric patients (6/7) were IVIG refractory and responded to rituximab. Six patients had favorable outcomes after immunotherapy with improvement ≥1 in the Inflammatory Neuropathy Cause and Treatment disability score.

Discussion: Pediatric patients with NF155-IgG4 AN display an aggressive disease course with rapid progression to disease nadir compared with adults. Sensory ataxia is less common in children, and they often respond to rituximab. It is crucial to consider autoimmune nodopathies in the differential diagnosis of pediatric patients with suspected inflammatory demyelinating polyneuropathy and to test for NF155-IgG4 antibodies because of their diagnostic and therapeutic implications.

Classification of evidence: This study provides Class IV evidence that in pediatric patients with NF155-IgG4 AN who are refractory to IVIG, rituximab treatment provided some benefit.

PubMed Disclaimer

Conflict of interest statement

P.J.B. Dyck reports research funding from Alnylam and Ionis. M.L. Mauermann has received research funding from IONIS and Alnylam. J. Mills has patents related to detection of monoclonal immunoglobulins by mass spectrometry and has filed patents on antibody biomarkers of neurological autoimmunity. D. Dubey has consulted for UCB, Immunovant, Argenx, Arialys and Astellas pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He is a named inventor on filed patent that relates to KLHL11 as marker of autoimmunity and germ cell tumor. He has patents pending for LUZP4-IgG, cavin-4-IgG and SKOR2-IgG as markers of neurological autoimmunity. He has received funding from the DOD (CA210208 and PR220430), David J. Tomassoni ALS Research Grant Program and UCB. All other authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.

Figures

Figure 1
Figure 1. MRI Lumbar Plexus Without and With Contrast of a Neurofascin IgG4 Seropositive Pediatric Patient
Axial T2 fat-suppressed images showed diffuse thickening, fascicular enlargement, and T2 hyperintense signal involving roots (A); lumbosacral plexus (B); nerves including obturator, femoral, and sciatic nerves (arrows) (C); peroneal and tibial nerves (arrows); and mild intramuscular edema and signal changes involving the vastus lateralis and vastus intermedius musculature (arrowheads) (D).
Figure 2
Figure 2. Sural Nerve Biopsy From a Neurofascin IgG4 Seropositive Pediatric Patient
Closely aligned teased nerve fibers stained with osmium tetroxide showing active axonal degeneration (arrow heads) and segmental demyelination (arrows) (A). Epoxy semithin cross-section stained with methylene blue showing severe multifocal fiber loss with active degenerating nerve fibers (red arrowheads, B) and thinly myelinated fibers (red arrows, C).
See this image and copyright information in PMC

References

    1. Shelly S, Klein CJ, Dyck PJB, et al. . Neurofascin-155 immunoglobulin subtypes: clinicopathologic associations and neurologic outcomes. Neurology. 2021;97(24):e2392-e2403. doi:10.1212/WNL.0000000000012932 - DOI - PMC - PubMed
    1. Yan WX, Nguyen T, Yuki N, et al. . Antibodies to neurofascin exacerbate adoptive transfer experimental autoimmune neuritis. J Neuroimmunology. 2014;277(1-2):13-17. doi:10.1016/j.jneuroim.2014.09.012 - DOI - PubMed
    1. Ogata H, Yamasaki R, Hiwatashi A, et al. . Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann Clin Transl Neurol. 2015;2(10):960-971. doi:10.1002/acn3.248 - DOI - PMC - PubMed
    1. Devaux JJ, Miura Y, Fukami Y, et al. . Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology. 2016;86(9):800-807. doi:10.1212/WNL.0000000000002418 - DOI - PMC - PubMed
    1. Kadoya M, Kaida K, Koike H, et al. . IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: clinical significance and diagnostic utility of a conventional assay. J Neuroimmunol. 2016;301:16-22. doi:10.1016/j.jneuroim.2016.10.013 - DOI - PubMed