Large-Scale Whole-Genome Analysis of HTLV-1-Associated Myelopathy Identified Hereditary Spastic Paraplegias

Naoki Takao; Naoko Yagishita; Natsumi Araya; Satoko Aratani; Junji Yamauchi; Katsunori Takahashi; Yasuo Kunitomo; Tomoo Sato; Masahiro Nakamori; Yosuke Kawai; Yosuke Omae; Katsushi Tokunaga; Fumihiko Matsuda; Satomi Mitsuhashi; Yoshihisa Yamano

doi:10.1212/NXG.0000000000200108

Large-Scale Whole-Genome Analysis of HTLV-1-Associated Myelopathy Identified Hereditary Spastic Paraplegias

Neurol Genet. 2024 Jan 29;10(1):e200108. doi: 10.1212/NXG.0000000000200108. eCollection 2024 Feb.

Authors

Affiliation

¹ From the Department of Neurology (N.T., J.Y., T.S., S.M., Y.Y.); Department of Rare Diseases Research (N.Y., N.A., S.A., J.Y., K. Takahashi, Y. Kunitomo, T.S., Y.Y.), Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki; Advanced Business Promotion Department (S.A.), Business Development Segment, LSI Medience Corporation, Tokyo; Department of Clinical Neuroscience and Therapeutics Hiroshima University Graduate School of Biomedical and Health Sciences (M.N.); Genome Medical Science Project (Y. Kawai, Y.O., K. Tokunaga), National Center for Global Health and Medicine, Tokyo; and Center for Genomic Medicine (F.M.), Kyoto University Graduate School of Medicine, Japan.

Abstract

Objectives: Distinguishing human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy from hereditary spastic paraplegia in patients infected with HTLV-1 is challenging due to overlapping clinical symptoms. The aim of this study was to explore the possibility that hereditary spastic paraplegia is inherently present in patients diagnosed with HTLV-1-associated myelopathy.

Methods: We performed whole-genome sequencing on 315 unrelated patients registered in the HTLV-1-Associated Myelopathy patient registry "HAM-net," from 2013 to 2022 in Japan. CSF inflammatory biomarkers, including CXCL10, were measured.

Results: We identified 5 patients with pathogenic variants in the genes RTN2, SPAST, VCP, and UBAP1, which are the known causes of hereditary spastic paraplegia. These patients had no family history of hereditary spastic paraplegia. The levels of CSF inflammatory biomarkers were lower than expected in these patients, compared with disease severity.

Discussion: Genetic analysis is useful for the differentiation of hereditary spastic paraplegia patients from HTLV-1-associated myelopathy patients, especially for the patients with low levels of CSF inflammatory markers. Here we report the presence of hereditary spinal cord diseases in patients diagnosed with HTLV-1-associated myelopathy and provides evidence that genetic analysis would be helpful in the diagnostic workflow.