AUTHOR=Chu Xujun , Xu Jin , Zheng Yilei , Liu Xiaoyu , Yuan Yun , Wu Rui 

TITLE=A novel KIDINS220 mutation associated with hereditary spastic paraplegia accompanied by severe peripheral neuropathy

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 19 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1684980

DOI=10.3389/fnins.2025.1684980

ISSN=1662-453X

ABSTRACT=ObjectivesMutations in KIDINS220 are known to cause hereditary spastic paraplegia (HSP) and SINO syndrome. However, the phenotypic and genotypic spectrum of KIDINS220-related disorders remains incompletely understood. Herein, we describe the clinical, electrophysiological, histopathological, and genetic features of a novel KIDINS220 sterile alpha motif (SAM) -like domain mutation identified in a Chinese family with HSP accompanied by severe peripheral neuropathy (PN).MethodsClinical data, electrophysiological characteristics, and sural nerve histopathology were analyzed in a 19-year-old Chinese male. Genetic testing was performed in his family by using whole-exome sequencing, mitochondrial genome testing, and Sanger validation. A comprehensive literature review was conducted to analyze the phenotypic and genetic data of previously reported cases with KIDINS220 variants up to July 2025.ResultsThe proband exhibited classical signs of autosomal dominant HSP accompanied by severe multifocal sensory-motor PN. The spinal cord MRI showed mild spinal cord thinning, while the brain MRI and nerve ultrasound examinations were normal. Electrophysiological study revealed absent sensory nerve responses and globally reduced motor conduction velocities. Sural nerve biopsy confirmed significantly reduced nerve fiber density, myelin defects, axonal degeneration, and mitochondrial abnormalities. A heterozygous KIDINS220 c.3668A > G (p. Glu1223Gly) mutation, located within the SAM domain, was identified in both the proband and his mother. A total of 42 cases from 11 cohorts were reviewed.ConclusionWe suggest that patients with KIDINS220 SAM domain mutation may present with HSP accompanied by severe, mixed axonal and demyelinating PN, expanding the existing spectrum of the clinical phenotypes and pathogenic variants of KIDINS220.