Motor unit number estimation in adult patients with spinal muscular atrophy treated with nusinersen

Background and purpose The aim was to assess the organization and short-term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen. Methods In this single-centre cross-sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age-matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4-8 months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle. Results The number of motor units (p < 0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (p < 0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (p = 0.005) and number of motor units (p = 0.03) compared to patients with SMA, accompanied by a larger median amplitude (p = 0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units (p = 0.046) accompanied by a decreased median amplitude (p = 0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores. Conclusion Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker

Four different synthetic peptides of proteolipid protein induce a distinct antibody response in MP4-induced experimental autoimmune encephalomyelitis

Here we studied the autoantibody specificity elicited by proteolipid protein (PLP) in MP4-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (MS). In C57BL/6 (B6) mice, antibodies were induced by immunization with one of the two extracellular and by the intracellular PLP domain. Antibodies against extracellular PLP were myelin-reactive in oligodendrocyte cultures and induced mild spinal cord demyelination upon transfer into B cell-deficient J(H)T mice. Remarkably, also antibodies against intracellular PLP showed binding to intact oligodendrocytes and were capable of inducing myelin pathology upon transfer into J(H)T mice. In MP4-immunized mice peptide-specific T(H)1/T(H)17 responses were mainly directed against the extracellular PLP domains, but also involved the intracellular epitopes. These data suggest that both extracellular and intracellular epitopes of PLP contribute to the pathogenesis of MP4-induced EAE already in the setting of intact myelin. It remains to be elucidated if this concept also applies to MS itself. (C) 2015 Elsevier Inc. All rights reserved

Amyloidogenicity assessment of transthyretin gene variants

Objective: Hereditary transthyretin-mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the transthyretin-gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non-pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in vitro approach. Methods: Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt-transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in vitro. As proof of principle, the assays were applied to transthyretin-Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants. Results: Transthyretin-Ala65Val showed a significantly higher amyloidogenic potential than wt-transthyretin, in both turbidity- and Thioflavin T-assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions. Interpretation: We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin-Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity

Antibody response after COVID‐19 vaccination in intravenous immunoglobulin‐treated immune neuropathies

BACKGROUND: This study assessed the prevalence of anti‐SARS‐CoV‐2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID‐19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)‐treated chronic immune neuropathies. METHODS: Forty‐six samples of different brands or lots of IVIg or subcutaneous IgG (SCIg) were analyzed for anti‐SARS‐CoV‐2 IgG using ELISA and chemiluminescent microparticle immunoassay (CMIA). Blood sera from 16 patients with immune neuropathies were prospectively analyzed for anti‐SARS‐CoV‐2 IgA, IgG, and IgM before and one week after IVIg infusion subsequent to consecutive COVID‐19 mRNA vaccine doses and after 12 weeks. These were compared to 42 healthy subjects. RESULTS: Twenty‐four (52%) therapeutic immunoglobulin samples contained anti‐SARS‐CoV‐2 IgG. All patients with immune neuropathies (mean age 65 ± 16 years, 25 % female) were positive for anti‐SARS‐CoV‐2 IgG after COVID‐19 vaccination. Anti‐SARS‐CoV‐2 IgA titers significantly decreased 12‐14 weeks after vaccination (p=0.02), IgG titers remained stable (p=0.2). IVIg did not significantly reduce intra‐individual anti‐SARS‐CoV‐2 IgA/IgG serum titers in immune neuropathies (p=0.69). IVIg‐derived anti‐SARS‐CoV‐2 IgG did not alter serum anti‐SARS‐CoV‐2 IgG decrease after IVIg administration (p=0.67). CONCLUSIONS: Our study indicates that IVIg does not impair the antibody response to COVID‐19 mRNA vaccine in a short‐term observation, when administered a minimum of two weeks after each vaccine dose. The infusion of current IVIg preparations that contain anti‐SARS‐CoV‐2 IgG does not significantly alter serum anti‐SARS‐CoV‐2 IgG titers

Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTR(v)) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTR(v) amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTR(v) amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers