The Clinical And Molecular Spectrum Of ZFYVE26-Associated Hereditary Spastic Paraplegia (SPG15)
Afshin Saffari1, Catherine Jordan1, Alisa Mo1, Bo Zhang1, Mustafa Sahin1, Craig Blackstone2, Edward Yang1, Darius Ebrahimi-Fakhari1
1Boston Children's Hospital, 2Massachusetts General Hospital
Objective:

To describe the clinical and molecular features of ZFYVE26-related hereditary spastic paraplegia (HSP) in order to raise awareness to this rare disease, facilitate an early diagnosis and promote clinical trial readiness.

Background:

ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare early-onset form of progressive HSP, characterized by progressive spasticity and a variety of other neurological symptoms.

Design/Methods:
44 individuals with bi-allelic variants in ZFYVE26 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.
Results:

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 ZFYVE26 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 scalesshowed moderate correlation with disease duration (SPRS score: 25.2±13.3 (SD), Rm2=0.51;, SPRS Spasticity Subscore: 7.3±4.3 (SD), Rm2=0.47; SPATAX disability score: 3.2±4.3 (SD), Rm2=0.63). NfL levels were significantly increased in HSP-ZFYVE26 patients and showed an inverse correlation with age.

Conclusions:

We delineate the clinical, neuroimaging and molecular spectrum of ZFYVE26-related HSP, demonstrate the progressive evolution of the disease and validate clinical rating scales as quantitative disease monitoring tools.

10.1212/WNL.0000000000201952