To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Ultrasound allows for a non-invasive structural assessment of nerves, muscles, and surrounding tissues, and therefore it is increasingly being used as a supplement to traditional electrodiagnostic studies. As investigators have begun to use ultrasound to explore peripheral nerves, it has become clear that conditions such as entrapment, hereditary neuropathies, acquired neuropathies, trauma, and nerve tumors result in an increase in nerve cross-sectional area. Reference values have not been published for the cross-sectional area of many nerves commonly studied in diseases of the peripheral nervous system, so our goal was to obtain reference values for the nerve cross-sectional area at the following sites: radial at antecubital fossa; radial at distal spiral groove; musculocutaneous in upper arm; trunks of the brachial plexus; vagus at carotid bifurcation; sciatic in distal thigh; tibial in popliteal fossa; tibial in proximal calf; tibial at ankle; peroneal in popliteal fossa; peroneal at fibular head; and sural in distal calf. Mean cross-sectional area, as well as side-to-side differences, are reported for each site, and qualitative data are provided to guide imaging at each site. The information provided in this study should serve as the starting point for quantitatively evaluating these nerve sites with ultrasound.
Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS, but much remains unknown about the strength of the association and the features of GBS in this setting. We reviewed 37 published cases of GBS associated with COVID-19 to summarize this information for clinicians and to determine whether a specific clinical or electrodiagnostic (EDx) pattern is emerging. The mean age (59 years), gender (65% male), and COVID-19 features appeared to reflect those of hospitalized COVID-19 patients early in the pandemic. The mean time from COVID-19 symptoms to GBS symptoms was 11 days. The clinical presentation and severity of these GBS cases was similar to those with non-COVID-19 GBS. The EDx pattern was considered demyelinating in approximately half of the cases. Cerebrospinal fluid, when assessed, demonstrated albuminocytologic dissociation in 76% of patients and was negative for severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) in all cases. Serum antiganglioside antibodies were absent in 15 of 17 patients tested. Most patients were treated with a single course of intravenous immunoglobulin, and improvement was noted within 8 weeks in most cases. GBS-associated COVID-19 appears to be an uncommon condition with similar clinical and EDx patterns to GBS before the pandemic. Future studies should compare patients with COVID-19-associated GBS to those with contemporaneous non-COVID-19 GBS and determine whether the incidence of GBS is elevated in those with COVID-19.
Pathological events are well characterized in amyotrophic lateral sclerosis (ALS) mouse models, but review of the literature fails to identify a specific initiating event that precipitates disease pathology. There is now growing consensus in the field that axon and synapses are first cellular sites of degeneration, but controversy exists over whether axon and synapse loss is initiated autonomously at those sites or by pathology in the cell body, in nonneuronal cells or even in nonmotoneurons (MNs). Previous studies have identified pathological events in the mutant superoxide dismutase 1 (SOD1) models involving spinal cord, peripheral axons, neuromuscular junctions (NMJs), or muscle; however, few studies have systematically examined pathogenesis at multiple sites in the same study. We have performed ultrastructural examination of both central and peripheral components of the neuromuscular system in the SOD1G93A mouse model of ALS. Twenty percent of MNs undergo degeneration by P60, but NMJ innervation in fast fatigable muscles is reduced by 40% by P30. Gait alterations and muscle weakness were also found at P30. There was no change in axonal transport prior to initial NMJ denervation. Mitochondrial morphological changes are observed at P7 and become more prominent with disease progression. At P30 there was a significant decrease in excitatory axo-dendritic and axo-somatic synapses with an increase in C-type axo-somatic synapses. Our study examined early pathology in both peripheral and central neuromuscular system. The muscle denervation is associated with functional motor deficits and begins during the first postnatal month in SOD1G93A mice. Physiological dysfunction and pathology in the mitochondria of synapses and MN soma and dendrites occur, and disease onset in these animals begins more than 2 months earlier than originally thought. This information may be valuable for designing preclinical trials that are more likely to impact disease onset and progression.
This report characterizes the clinical features of 16 cases of stroke associated with IV immunoglobulin infusions. Fourteen of the strokes occurred within 24 hours of an infusion and 50% of the patients were receiving IV immunoglobulin for the first time. Nine patients had multifocal infarctions. All but one of the patients had stroke risk factors.
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