Update on Genetic Chorea
TL;DR
The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful.
Abstract
Chorea is a symptom of numerous pathophysiologically and clinically heterogeneous genetic conditions. A number of developments have been made in this field over the last years linked to improved genomic testing, large cohort collaborations and improved understanding of the molecular mechanisms. This review aims to provide an update on the new genetic conditions and phenotypes linked to chorea disorders, their modification factors and pathophysiological background. Several novel genetic conditions have been linked to chorea over the last 3 years, including mutations in FTH1, NAA60, ACBD6 or TOR1AIP2. Also, novel phenotypes have been established and linked to chorea, such as Adult-onset Neurodegeneration in Nucleotide Excision Repair Disorder (NERD-ND). Major advances have been made in understanding of the pathophysiological role of somatic instability in HD. Striatal pallidal neurons (SPNs) with 150–500 + CAG repeats seem to lose positive and then negative features of neuronal identity, de-repress senescence/apoptosis genes, ultimately leading to cell death. Improved recognition of the genetic background of chorea leads to more effective diagnostic processes, better prognostication and improved personalized treatment. The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful. This has potential major therapeutic implications not only in HD but also in other neurological repeat expansion disorders.