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.

Keywords: C9ORF72; anticipation; expanded repeats; myotonic dystrophy; polyglutamine diseases; repeat instability; spinocerebellar ataxia; trinucleotide.

Figure 1.. Schematic of gene showing repeat expansions that cause neurological diseases

Repeat sequences linked to the indicated diseases are placed schematically into the appropriate gene locations. The differing sizes of the associated triangles roughly reflect the range of repeat expansion sizes in each disease. *SCA12 repeat is actually in an intron that also has promoter elements.

Figure 2.. Relationship of repeat length to disease features in spinocerebellar ataxia type 3 (SCA3)

Normal CAG repeat length in SCA3 is 12 to ~44, with disease repeats ranging from ~60–87. Clinical subtypes 1 (dystonia), 2 (ataxia), and 3 (weakness) tend to be associated with the range of indicated repeat lengths. Rare intermediate repeat lengths may be associated with restless legs syndrome.

Figure 3.. Normal and disease repeat lengths for the CAG/polyglutamine diseases

Normal (green), incompletely penetrant (yellow) and fully penetrant (red) repeat lengths are shown for each disease. Deepening color of red illustrates increased disease severity and earlier age of onset with longer repeat lengths. Arrows illustrate that the longest disease repeats in spinocerebellar ataxia type 2 (SCA2), SCA7 and Huntington disease are >100 repeats. Gray regions represent size range of intermediate length repeats that may be prone to further expansion. High normal SCA2 alleles (orange) are a risk factor for ALS. At SCA1 locus, normal repeats can be longer when they are interrupted by CAT residues. DRPLA, dentatorubral-palliodoluysian atrophy; SBMA, spinobulbar muscular atrophy * Normal repeat length in SCA1 and SCA6 are modifiers of age of onset, and SCA6 normal repeat length is also a modifier of age of onset in SCA2. # In SCA2 disease repeats interrupted by CAA can be associated with dominantly inherited Parkinson disease rather than ataxia. ^ Normal repeat in SCA17 is an imperfect CAG repeat interrupted with CAA residues.