Adaptor protein complex 4‐associated hereditary spastic paraplegia (AP‐4‐HSP) is caused by pathogenic biallelic variants in AP4B1, AP4M1, AP4E1, and AP4S1.
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.
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.