Kiernan, Matthew C.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Abstract Objectives: The objective of the study is to distinguish the mechanisms of disease for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN), which we believe to be fundamentally different. However, distinguishing the mechanisms is more difficult when the presentation of CIDP is motor-predominant, focal, or asymmetric. Methods: We describe 3 focal, motor-predominant, representative cases that could be interpreted on clinical and/or electrophysiological grounds as either MMN or focal CIDP, and present pathological findings. Results: We highlight pathological differences in these cases, and provide an argument that CIDP and MMN are distinct entities with different pathophysiological mechanisms—chronic demyelination for CIDP, and an immune-mediated attack on paranodal motor axons for MMN. Conclusions: Based on clinical evaluation, electrophysiology, and nerve biopsy pathology, we can divide the conditions into inflammatory demyelinating neuropathy (focal CIDP) versus chronic axonal neuropathy (MMN). The divergent pathological findings provide further evidence that CIDP and MMN are fundamentally different disorders.