Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Brenner et al. show that mutations in a C-terminal hotspot of kinesin-5A (KIF5A) can cause a classical ALS phenotype. Experiments using patient-derived cell lines suggest haploinsufficiency as the molecular genetic mechanism. This underlines the relevance of intracellular transport processes for ALS, and is important for clinico-genetic diagnosis and counselling.

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Electromyographic mirror activity (MA) refers to involuntary activation of the non-active limb during intended strictly unilateral movements of the other limb. MA occurs in the majority of healthy adults but little is known about its neurophysiological foundation. Here we examined in healthy adults the hypothesis that transcallosal interhemispheric inhibition (IHI) between the primary motor cortices determines the extent to which MA occurs. IHI was tested by an established paired transcranial magnetic stimulation protocol [A. Ferbert et al. (1992) J. Physiol. (Lond.), 453, 525-546]. In a first experiment we found that the magnitudes of IHI and MA were inversely correlated. In a second experiment we sought to establish a more causative relation by exploring the changes induced by low-frequency repetitive transcranial magnetic stimulation of primary motor cortex on IHI and MA. These changes were also significantly inversely correlated, i.e. a repetitive transcranial magnetic stimulation-induced increase in IHI was associated with a decrease in MA, and a decrease in IHI was associated with an increase in MA. These results provide strong and consistent evidence that transcallosal inhibitory interhemispheric interaction provides a significant route by which unwanted MA during intended unimanual motor tasks can be controlled.

Lung cancer is the leading cause of cancer mortality rate worldwide, mainly because of the presence of metastatic disease at the time of diagnosis. Early detection of lung cancer improves prognosis, and towards this end, large screening trials in high-risk individuals have been conducted since the past century. Despite all efforts, the need for novel (complementary) lung cancer diagnostic and screening methods still exists. In this review, we focus on the assessment of lung cancer-related biomarkers in sputum in the past decennium. Besides cytology, mutation and microRNA analysis, special attention has been paid to DNA promoter hypermethylation, of which all available literature is summarised without time restriction. A model is proposed to aid in the distinction between diagnostic and risk markers. Research on the use of sputum for non-invasive detection of early-stage lung cancer has brought new insights and advanced molecular techniques. The sputum shows a promising potential for routine diagnostic and possibly screening purposes.

Background and purpose: The spectrum of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), includes different neurologic manifestations of the central and peripheral nervous system. Methods: From March through April 2020, in two university hospitals located in western Switzerland, we examined three patients with Guillain-Barr e syndrome (GBS) following SARS-CoV-2. Results: These cases were characterized by a primary demyelinating electrophysiological pattern (Acute inflammatory demyelinating polyneuropathy or AIDP) and a less severe disease course compared to recently published case series. Clinical improvement was observed in all patients at week five. One patient was discharged from hospital after full recovery with persistence of minor neurological signs (areflexia). Two of the three patients remained hospitalized: one was able to walk and the other could stand up with assistance. Conclusions: We report three cases of typical GBS (AIDP) occurring after SARS-CoV-2 infection and presenting with a favourable clinical course. Given the interval between COVID-19-related symptoms and neurological manifestations (mean of 15 days) we postulate a secondary immune-mediated mechanism rather than direct viral damage.

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