A Homoplasmic MT‐TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia

Abstract Background Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases. Objectives To identify novel genetic causes of HSP. Methods Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family. Results We found a homoplasmic MT‐TV (mitochondrial tRNA Val ) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth‐generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT‐TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria. Conclusions The rare MT‐TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.