Repeat expansion diseases

Abstract

More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.

Comparison of the Huntington's Disease like 2 and Huntington's Disease Clinical Phenotypes

“…The two groups had very similar inverse correlations (HDL2 [R 2 = 0.74], HD [R 2 = 0.78]), which has been previously noted in a systematic review of HDL2 cases . Another feature that many CAG repeat disorders share is that they manifest clinically at a threshold of 35 to 40 triplet repeats . This has been shown to be the threshold that polyglutamine proteins begin to aggregate in vitro studies .…”

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

“…A pathogenic repeat expansion was also identified in one family (1.5%) by STRetch (Tables and ; Table S5). This expansion is associated with Spinocerebellar ataxia type 8 (Mundwiler & Shakkottai, ; Paulson, ) and was subsequently confirmed by clinical testing in the proband.…”

“…Hereditary spinocerebellar ataxia (dominant SCA and recessive SCAR) and spastic paraplegia (HSP) are neurodegenerative disorders affecting the cerebellum, its pathways, and the corticospinal tracts that can result from mutations in one of the hundreds of genes (Online Mendelian Inheritance in Man [OMIM], https://www.omim. org/; OMIM, 2019). Both disorders manifest high degrees of phenotypic heterogeneity even with common specific causal mutations, necessitating genomic testing strategies to identify the relatively rare causal mutations that are pervasive in both disorders and heterogeneous in presentation (Anheim, Tranchant, & Koenig, 2012;Benini, Ben Amor, & Shevell, 2012;Brusse, Maat-Kievit, & van Swieten, 2007;Fogel & Perlman, 2006Fogel, Satya-Murti, & Cohen, 2016;Klockgether, 2010;Manto & Marmolino, 2009).…”

Long-read sequencing identified repeat expansions in the 5′UTR of theNOTCH2NLCgene from Chinese patients with neuronal intranuclear inclusion disease

“…As scientists explore the underlying mechanisms of various repeat expansion diseases, it has become increasingly clear that they cluster in groups sharing clinical and molecular features. 11 Many features of NOTCH2NLC repeat-mediated disease indicate that it belongs to one such cluster: neurodegenerative disorders caused by GC-rich repeats residing in nonprotein coding regions of the respective disease genes. Wellknown members of this class include fragile X-associated tremor ataxia syndrome (FXTAS) and C9ORF72-mediated frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ ALS).…”