Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats 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 lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Gene symbol: SCN5A.

A 8-year-old white female was referred to our attention for a suspected Long QT syndrome. The clinical history was negative for cardiac events. The prolongation of the QTc was initially observed after assumption oi Qf proiongi.rg drugs (clarithromycin). However, even without those drugs and with normal potassium values, the QTc wai still prolonged (QTc 490 ms in D2) and during the recovery phase of exercise a iurther prolongation of the QT, associated with the appearance of notched T waves in V2-V3, was observed. Echocardiography showed normal features. LQTS genes were screened through DHPLC and sequence analysis. A double mutation was identified, one on KCNQ1 (A372D), already described as a disease-causing mutation and a second novel one (R1175C) in the intra-cellular loop between D2 and D3 on SCNSA. This second mutation is in a highly conserved aminoacid and was not identified in 150 controls

Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia

Abstract Catecholaminergic polymorphic ventricular tachycardia is a potentially lethal disease characterized by adrenergically mediated ventricular arrhythmias manifested especially in children and teenagers. Beta-blockers are the cornerstone of therapy, but some patients do not have a complete response to this therapy and receive an implantable cardioverter-defibrillator (ICD). Given the nature of catecholaminergic polymorphic ventricular tachycardia, ICD shocks may trigger new arrhythmias, leading to the administration of multiple shocks. We describe the long-term efficacy of surgical left cardiac sympathetic denervation in three young adults with catecholaminergic polymorphic ventricular tachycardia, all of whom had symptoms before the procedure and were symptom-free afterward