Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4‐Related Hereditary Spastic Paraplegia

Abstract Background Adaptor protein complex 4‐associated hereditary spastic paraplegia (AP‐4‐HSP) is caused by pathogenic biallelic variants in AP4B1 , AP4M1 , AP4E1, and AP4S1 . Objective The aim was to explore blood markers of neuroaxonal damage in AP‐4‐HSP. Methods Plasma neurofilament light chain (pNfL) and glial fibrillary acidic protein (GFAP) levels were measured in samples from patients and age‐ and sex‐matched controls (NfL: n = 46 vs. n = 46; GFAP: n = 14 vs. n = 21) using single‐molecule array assays. Patients' phenotypes were systematically assessed using the AP‐4‐HSP natural history study questionnaires, the Spastic Paraplegia Rating Scale, and the SPATAX disability score. Results pNfL levels increased in AP‐4‐HSP patients, allowing differentiation from controls (Mann‐Whitney U test: P = 3.0e‐10; area under the curve = 0.87 with a 95% confidence interval of 0.80–0.94). Phenotypic cluster analyses revealed a subgroup of individuals with severe generalized‐onset seizures and developmental stagnation, who showed differentially higher pNfL levels (Mann‐Whitney U test between two identified clusters: P = 2.5e‐6). Plasma GFAP levels were unchanged in patients with AP‐4‐HSP. Conclusions pNfL is a potential disease marker in AP‐4‐HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.