Amyotrophic lateral sclerosis and spinocerebellar ataxia type 2: A familial case report

Introduction While separate and phenotypically distinct diseases, spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a genetic association via a trinucleotide (CAG) repeat expansion in the ATXN2 gene [1,2]. While ubiquitin-positive cytoplasmic inclusions of trans-activate response DNA-binding protein (TARDBP or TDP-43) are known to be pathognomonic for ALS, these TDP-43 inclusions are also seen in the cytoplasm of motor neurons in SCA2. This elucidates an interconnected pathway of gene overexpression and protein toxicity [2,3]. Full expansion is associated with an increased presence of TDP-43 inclusions in the cytoplasm of degenerating neurons [4]. While the genetic association between ALS and SCA2 via the ATXN2 gene is well established, there are few reports demonstrating intrafamilial phenotypic variability of ATXN2 mutations. Here we report a family with separate and distinct phenotypes via repeat expansions in ATXN2, whose presentations do not align with their expected phenotypes based on CAG repeat size.