Advances in the genetic classification of amyotrophic lateral sclerosis

Abstract

Purpose of review Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease where disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture which will be necessary for comprehensive disease subclassification. Recent findings We summarise recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach including clinicians, geneticists and pathologists. Summary The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.

Piggybacking on the Cholera Toxin: Identification of a CTB-Binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons

“…In a mouse ALS model, transgenic overexpression of the calcium-binding protein parvalbumin slowed progression of symptoms and increased survival when compared to the ALS mice with normal levels of expression . In humans, such transgenesis is not feasible, particularly since genetic causes of ALS remain unknown and most cases are classified as sporadic . Therefore, utilizing parvalbumin (or similar proteins with neuroprotective potential) as a payload in the CTB–Affimer complex could enable its delivery to motor neurons and so reduce their vulnerability to degeneration in ALS.…”

Mitochondrial function determines severity but not risk of amyotrophic lateral sclerosis

“…ALS is a result of specific toxicity to motor neurons which leads to death, usually from respiratory failure, within 2-5 years 2 . The majority of ALS cases are thought to be the product of a gene-environment interaction 1 . In all cases described to date, genetic risk is present from conception but disease does not develop until much later; most patients do not develop symptoms until their 6th decade.…”

Implications of confirmed de novo pathogenic SOD1 mutations

“…This work lays the foundation for such a study. It is possible that somatic mutations play a role in the apparent disparity between broad-sense heritability for ALS which is measured at ~50%, and the much smaller (<10%) single-nucleotide polymorphism (SNP) based heritability3 measured from peripheral blood.…”