Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland

Background: We investigated the phenotypes and genotypes of a cohort of ‘long-surviving’ individuals with motor neuron disease (MND) to identify potential targets for prognostication. Methods: Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls. Results: 58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions. Conclusions: Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication

Genotypes and phenotypes of motor neuron disease: an update of the genetic landscape in Scotland

Background: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype–phenotype associations. Methods: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology. Results: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant. Conclusions: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments

Clinical trials in amyotrophic lateral sclerosis:a systematic review and perspective

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of phase II, phase II/III and phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15000 people with amyotrophic lateral sclerosis. 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis

Lineage Analysis of Circulating Trypanosoma cruzi Parasites and Their Association with Clinical Forms of Chagas Disease in Bolivia

Around 30–50% of Trypanosoma cruzi infections in Latin America cause chronic Chagas disease 10–30 years after the primary infection due to lack of effective treatment. The major clinical complications associated with chronic Chagas disease are cardiac myositis (leading to cardiac failure), and autonomous neuroplexus degeneration of the digestive tract that can cause megacolon or megaesophagus. Therefore, there are three major clinical forms of Chagas disease; cardiac, digestive and indeterminate (asymptomatic). The parasites, which can infect humans as well as other mammals, are transmitted by species of triatomines commonly found in the Americas. The parasite is divided in at least six discrete typing units: TcI, TcIIa–e. In humans, the TcI is mainly observed in Central America and northern parts of South America while the TcIIb/d/e is confined mainly to the southern cone of Latin America. We determined which DTU were prevalent in chronic patients in Bolivia, where the three clinical forms and several DTUs of the parasites are present, in order to determine whether there was a link between a particular parasite DTU and a particular clinical outcome. We found a vast majority of TcIId but its kDNA polymorphism showed no association with any of the clinical manifestations of chronic Chagas

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament