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

Abstract

BackgroundAdaptor protein complex 4‐associated hereditary spastic paraplegia (AP‐4‐HSP) is caused by pathogenic biallelic variants in AP4B1, AP4M1, AP4E1, and AP4S1.ObjectiveThe aim was to explore blood markers of neuroaxonal damage in AP‐4‐HSP.MethodsPlasma 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.ResultspNfL 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.ConclusionspNfL is a potential disease marker in AP‐4‐HSP and can help differentiate between phenotypic subgroups. © 2023 International Parkinson and Movement Disorder Society.

Early Diagnosis of AP5Z1/SPG48 Spastic Paraplegia: Case Report and Review of the Literature

“…Childhood-onset hereditary motor disorders are a challenge in neuropediatric clinics because of the nonspecific presentations, the levels of overlap with cerebral palsy and neurodevelopmental disorders, the often-incomplete progression of psychomotor abilities precluding reliable examination, and the relative lack of characteristic neuroimaging features. To date no consensus on diagnostic strategies for pediatric HSP cases has been reached and, because of the limited information on sensitive-to-change serum biomarkers, 12 the diagnosis is based mostly on genetic screening. However, early diagnosis, even in the premotor stage, is critical, making it possible to propose appropriate clinical interventions also geared at supporting psychomotor development, evaluate the need for orthoses, and promote the acquisition of basic autonomy (through play with peers, school attendance, reduction of falls, etc.).…”

Plasma Neurofilaments: Potential Biomarkers of SPG11‐Related Hereditary Spastic Paraplegia

“…2 Elevated plasma NfL was reported in pediatric cohorts of ZFYVE26-associated and AP4-related HSP. 3,4 As genotype-specific neurofilament analyses for adult HSP cohorts have been sparse, we here (1) analyzed levels of plasma NfL and NfH and (2) explored the temporal dynamics of NfL and NfH in a prospective HSP cohort of an academic movement disorders outpatient center.…”