Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4.

OBJECTIVE: While the anticipated rise of disease-modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. METHODS: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1-year follow-up and 2-year follow-up visit. RESULTS: Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our cross-sectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels. INTERPRETATION: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.

A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype.

BACKGROUND: Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. METHODS: Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. RESULTS: A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. CONCLUSION: De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.