DPP6 IS ASSOCIATED WITH SUSCEPTIBILITY TO PROGRESSIVE SPINAL MUSCULAR ATROPHY

Progressive spinal muscular atrophy (PMA) is a disorder characterized by loss of lower motor neurons resulting in progressive muscle weakness. It has been debated whether PMA is a distinct disease entity or should be considered a subtype of amyotrophic lateral sclerosis (ALS). PMA can progress to ALS and the disease course of PMA can be equally relentless, with death due to respiratory failure within 3 years.¹ Familiar patients with ALS with mutations in SOD1 can lack UMN signs. Furthermore, pathologic studies of PMA have shown involvement of the corticospinal tract and ubiquinated inclusions, as also observed in ALS.

Sporadic ALS and PMA are complex diseases, with environmental and genetic factors contributing to disease susceptibility. Mutations in ALS cases have been found in SOD1, ANG, and TDP-43. However, in the majority of cases the genetic background of sporadic ALS is unknown. Over the last 2 years, several genome-wide association studies (GWAS) have been performed in ALS and have highlighted the discovery of three novel candidate genes, including DPP6.² This association has now been replicated twice by independent studies.^3,4

Considering the clinical and pathologic overlap between ALS and PMA, we investigated the hypothesis that genetic variation in DPP6 may be a risk factor for PMA.