The neurofilament light chain gene (NEFL) mutation Pro22Ser can be associated with mixed axonal and demyelinating neuropathy

We report the detailed clinical, electrophysiological and molecular analysis of a patient with Charcot-Marie-Tooth (CMT) disease. DNA sequencing of the coding sequences of the neurofilament light chain polypeptide (NEFL) gene revealed a c.64C > T heterozygous, missense mutation resulting in a Pro22Ser amino acid substitution. Clinical and electrophysiological studies revealed a mixed axonal and demyelinating neuropathy, with widespread demyelination involving both proximal and distal nerve segments. Mutations at this site in the NEFL gene have been previously linked to an axonal neuropathy or distal nerve demyelination. Our results emphasize the complexity of genotype–phenotype correlations in CMT and underline the possible importance of host factors and gene interactions in the development of clinical phenotypes.     

Serum neurofilament light chain (NFL) remains unchanged during electroconvulsive therapy

Abstract

Objectives: Although there is consistent evidence that electroconvulsive therapy (ECT) is safe and well tolerated by the majority of patients, some authors still accuse ECT to inevitably cause brain damage and permanent memory loss, assertions that may increase patients’ worries about a useful treatment. Recently, the measurement of neurofilament light chain (NFL) in peripheral blood was technically implemented, permitting longitudinal analysis of this biomarker for axonal damage. NFL is part of the axonal cytoskeleton and is released into the CSF and peripheral blood in the context of neuronal damage.

Methods: In our study, blood from 15 patients with major depressive disorder receiving ECT was collected before the first ECT as well as 24?h and seven days after the last ECT, respectively. NFL concentrations were analysed using the ultrasensitive single molecule array (Simoa) technology.

Results: NFL concentrations did not differ between patients and healthy controls, and there was no significant change in NFL levels in the course of ECT. On the contrary, we even found a slight decrease in absolute NFL concentrations.

Conclusions: Our study confirms the safety of ECT by using a most sensitive method for the detection of NFL in peripheral blood as a biomarker of neuronal damage.     

The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy

Charcot-Marie-Tooth disease comprises a heterogeneous group of hereditary neuropathies which fall into two main groups: demyelinating CMT1 with reduced nerve conduction velocity and axonal CMT2 with normal nerve conduction velocity. The neuropathological features correspond in most cases to this classification. Four genes were recently identified to cause autosomal dominant CMT2, including the neurofilament light gene. Thus far, only few mutations have been reported in neurofilament light involving eight amino acids of the gene. We identified a novel mutation, Glu397Lys, in a conserved motive signaling the end of the rod domain. The affected family members from three generations showed strikingly different clinical phenotypes, including weakness of the lower extremities, foot deformities, and deafness. The mutation was associated with nerve conduction velocities ranging from 27 m/s in a 25-year-old female to 43 m/s in an 82-year-old male in the lower extremity motor nerves. Sural nerve biopsies of two affected subjects were analyzed by light and electron microscopy. The pathological changes consisted of a reduction of predominantly large myelinated nerve fibers and various stages of onion bulb formation as typically seen in CMT1. This correlative study further confirms that neurofilament light gene mutations cause a wide clinical spectrum. Thus, analysis of the neurofilament light gene should not be restricted to pure axonal neuropathies.     

Longitudinal serum neurofilament light chain (sNfL) concentration relates to cognitive function in multiple sclerosis patients

Journal of Neurology - Serum neurofilament light chain (sNfL) may be used as a biological marker of disease progression in multiple sclerosis (MS), although longitudinal studies correlating...     

Cortical microstructural correlates of plasma neurofilament light chain in Huntington's disease

IntroductionHuntington's disease (HD) is a severe neurodegenerative disorder with no effective treatment. Minimally-invasive biomarkers such as blood neurofilament light chain (NfL) in HD are therefore needed to quantitatively characterize neuronal loss. NfL levels in HD are known to correlate with disease progression and striatal atrophy, but whether they also reflect cortical degeneration remains elusive.MethodsIn a sample of 35 HD patients, we characterized the cortical macro (cortical thickness) and microstructural (increased intracortical diffusivity) correlates of plasma NfL levels. We further investigated whether NfL-related cortical alterations correlated with clinical indicators of disease progression.ResultsIncreased plasma NfL levels in HD reflected posterior-cortical microstructural degeneration, but not reduced cortical thickness (p < 0.05, corrected). Importantly, these imaging alterations correlated, in turn, with more severe motor, cognitive and behavioral symptoms.ConclusionPlasma NfL levels may be useful for tracking clinically-meaningful cortical deterioration in HD. Additionally, our results further reinforce the role of intracortical diffusivity as a valuable imaging indicator in movement disorders.     

Elevated serum neurofilament light chain in children autism spectrum disorder: A case control study

ObjectiveWe aimed to assess serum neurofilament light chain (sNfL) levels in autism spectrum disorder (ASD) and to investigate whether they are related to the severity of disease.MethodsThe cohorts consisted of 166 children aged 3–8 (83 children diagnosed with ASD and 83 children with typically-developing). sNfL were analyzed using Single Molecule Array (Simoa) technology. ASD symptom severity was assessed according to the Chinese version of the Childhood Autism Rating Scale (CARS) score.ResultsThe mean age of those included ASD was 5.1 years (standard deviations [S.D.]: 1.7) and 78.3 % were boys. The mean (SD) sNfL concentrations were significantly (P < 0.001) higher in ASD than in TP children (10.2[5.0] pg/mL and 7.1[3.2]pg/mL). For each 1 pg/mL increase of sNfL, the risk of ASD would increase by 19 % (with the OR _unadjusted of 1.19 [95 % CI 1.10–1.29], P < 0.001) and 11 % (with the OR _adjusted of 1.11 [1.03–1.23], P < 0.001), respectively. sNfL concentrations in children with severe ASD were higher than in those children with mild-to-moderate ASD (12.4[5.1] pg/mL vs. 8.3[4.2]pg/mL; P < 0.001). Among ASD cases, each 1 pg/mL increase of sNfL is associated with 20 % higher unadjusted or 11 % higher adjusted odds, respectively, of severe (vs. mild-to-moderate) ASD.ConclusionsThe data showed that sNfL was elevated in ASD and related to symptom severity, suggesting that sNfL may play a role in ASD progression.     

Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients

BackgroundLittle is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.MethodsSera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single‐molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.ResultssNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale‐revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003).ConclusionsIn this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.     

CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders

Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus–myoclonus syndrome (OMS) (n = 234) was compared to pediatric non-inflammatory neurological controls (n = 84) and other inflammatory neurological disorders (OIND) (n = 44). Only CSF NFL was elevated in untreated OMS versus controls (+ 83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy.     

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis—a cross-sectional multicenter study

Background and purpose

The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV).

Methods

A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale.

Results

In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46–3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5–10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001).

Conclusions

The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.     

Validity of serum neurofilament light chain as a prognostic biomarker of disease activity in multiple sclerosis

Journal of Neurology - Multiple sclerosis (MS) is a chronic demyelinating and neuroinflammatory disease of the human central nervous system with complex pathoetiology, heterogeneous presentations...     

The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer's disease

BACKGROUND/AIMS: Attempting to improve the cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD), the neurofilament heavy chain isoform, NfH(SMI35) was compared to other CSF markers [total tau, phospho-tau, amyloid beta 1-42 (Abeta42), the ratio of amyloid beta fragments Abeta42/Abeta40 (Abeta ratio)]. METHODS: CSF levels were determined in patients with AD (n = 109), mild cognitive impairment (MCI, n = 25), frontotemporal dementia (n = 15), vascular dementia (VD, n = 41), and controls (n = 58). RESULTS: CSF NfH(SMI35) was elevated in AD and VD as compared to controls (p < 0.05). Total tau was higher in AD as compared to controls (p < 0.05). CSF phospho-tau was elevated in AD as compared to controls and VD (p < 0.05 each). CSF Abeta42 and Abeta ratios in AD were lower than in MCI and controls (p < 0.05 each). CONCLUSION: The diagnostic potential of NfH(SMI35) is not superior to that of other CSF markers.