Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

Abstract

Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease-modifying gene-stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long-read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)•(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult-onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9-61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late-onset slowly progressive pan-cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4-aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B.

Keywords: 4-aminopyridine; FGF14; GAA-FGF14 ataxia; cerebellar ataxia; genetics; repeat expansion disorder; therapy.

FIGURE 1

Length and motif polymorphism of the FGF14‐SCA27B repeat locus. (A) Diagram of the FGF14 gene, isoform 1b showing the location of the (GAA)_n•(TTC)_n repeat locus in the first intron (GRCh38, chr13:102,161,575‐102,161,726) with representation of the normal alleles, alleles of uncertain pathogenicity, incompletely penetrant alleles, pathogenic alleles and likely non‐pathogenic non‐GAA‐pure alleles, such as (GAAGGA)n _n and [(GAA) _n (GCA) _m ] _z . (B) Swarm plot showing the allele distribution of the FGF14 repeat locus in 2191 non‐ataxic controls (4382 chromosomes) as assessed by PacBio HiFi long‐read sequencing. The colour of the data points is a function of the GAA repeat motif purity, with dark blue indicating pure and lighter blue impure/interrupted motif (a hue scale is shown on the right y axis). The dashed grey line and the shaded grey area indicate the incompletely penetrant range of (GAA)_250–300 repeat units, and the dashed red line represents the pathogenic threshold of (GAA)_>300 repeat units. Two non‐GAA‐pure alleles of over 800 repeat units were excluded for clarity.

FIGURE 2

Geographic distribution of identified patients with spinocerebellar ataxia 27B. Patients with spinocerebellar ataxia 27B (SCA27B) have now been identified in 18 countries around the world, shown in orange in the world map.