The Clinical And Molecular Spectrum Of ZFYVE26-Associated Hereditary Spastic Paraplegia (SPG15) (P13-11.005)

Abstract

<h3>Objective:</h3> To describe the clinical and molecular features of <i>ZFYVE26</i>-related hereditary spastic paraplegia (HSP) in order to raise awareness to this rare disease, facilitate an early diagnosis and promote clinical trial readiness. <h3>Background:</h3> <i>ZFYVE26</i>-associated hereditary spastic paraplegia (HSP-<i>ZFYVE26</i>, SPG15) is a rare early-onset form of progressive HSP, characterized by progressive spasticity and a variety of other neurological symptoms. <h3>Design/Methods:</h3> 44 individuals with bi-allelic variants in <i>ZFYVE26</i> were recruited from our Registry for Early-onset Hereditary Spastic Paraplegia (NCT04712812). A cross-sectional analysis of demographic, clinical and molecular data was conducted using a standardized questionnaire. Results were compared to 65 previously published cases. Disease severity was quantified using the Spastic Paraplegia Rating Scale (SPRS), the SPRS Spasticity Subscore and the SPATAX Disability Score. Plasma neurofilament light chain (NfL) concentrations were measured using the SiMoA HD-X Analyzer. <h3>Results:</h3> While symptom onset was in early childhood, a molecular diagnosis was reached at a median age of 14.4 years (IQR=6), indicating a significant diagnostic delay. 45 distinct variants in <i>ZFYVE26</i> were identified. Most patients presented with developmental delay or learning disabilities. This preceded the onset of motor symptoms by several years. Spasticity in the lower extremities involved the ankles first, with subsequent progression to proximal areas. Extrapyramidal movement disorders and neurogenic bladder dysfunction were common. Brain MR imaging showed a thin corpus callosum and signal changes of the anterior forceps as well as non-specific cortical and cerebellar atrophy in a subset. Clinical rating scales showed moderate correlation with disease duration (SPRS score: 25.2±13.3 (SD), <i>R</i>_m²=0.51;, SPRS Spasticity Subscore: 7.3±4.3 (SD), <i>R</i>_m²=0.47; SPATAX disability score: 3.2±4.3 (SD), <i>R</i><i>_m</i>²=0.63). NfL levels were significantly increased in HSP-<i>ZFYVE26</i> patients and showed an inverse correlation with age. <h3>Conclusions:</h3> We delineate the clinical, neuroimaging and molecular spectrum of <i>ZFYVE26</i>-related HSP, demonstrate the progressive evolution of the disease and validate clinical rating scales as quantitative disease monitoring tools. <b>Disclosure:</b> Dr. Saffari has nothing to disclose. Miss Jordan has nothing to disclose. Dr. Mo has nothing to disclose. Bo Zhang has nothing to disclose. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regenxbio . Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Centene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for PTEN Research. Dr. Sahin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Sahin has received research support from NIH. The institution of Dr. Sahin has received research support from Tuberous Sclerosis Alliance. The institution of Dr. Sahin has received research support from Charities Aid Foundation. The institution of Dr. Sahin has received research support from Simons Foundation Autism Research Initiative. The institution of Dr. Sahin has received research support from Aucta Pharmaceuticals . The institution of Dr. Sahin has received research support from Loulou Foundation. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as a Consultant for FIrstThought. Dr. Blackstone has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Asha Therapeutics. Dr. Blackstone has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Ficksman &amp; Conley, LLP. The institution of Dr. Yang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Syngeos. Dr. Ebrahimi-Fakhari has received personal compensation in the range of $0-$499 for serving as a Consultant for Alcimed Inc.. The institution of Dr. Ebrahimi-Fakhari has received research support from CureAP4 Foundation, CureSPG50 Foundation, Spastic Paraplegia Foundation, Manton Center for Orphan Disease Research, BPAN Warriors Foundation, NIH/NINDS. Dr. Ebrahimi-Fakhari has received publishing royalties from a publication relating to health care.