An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches

Abstract

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Keywords: RFC1; THAP11; Ataxia; Cerebellar ataxia; Spinocerebellar ataxia type 27B; Spinocerebellar ataxia type 4.

Fig. 1

Recently described short tandem repeat expansions causing cerebellar ataxia with key diagnostic clues

Fig. 2

Flowchart of current suggested testing approach for genetic diagnosis of adult-onset hereditary cerebellar ataxia. [AD: autosomal dominant; AR: autosomal recessive; DRPLA: dentatorubral-pallidoluysian atrophy; FRDA: Friedreich ataxia; FXTAS: fragile X-associated tremor/ataxia syndrome; mtDNA: mitochondrial DNA; NGS: next-generation sequencing; SCA: spinocerebellar ataxia; WES: whole exome sequencing; WGS: whole genome sequencing; XL: X-linked]

Fig. 3

Potential future testing approach for genetic diagnosis of adult-onset hereditary cerebellar ataxia using advanced genomic technologies. [LRS: long-read sequencing; sr-WGS: short-read whole genome sequencing]

Fig. 4

Contributing factors and potential solutions for the diagnostic gap in hereditary cerebellar ataxias. [HSP: hereditary spastic paraplegia; LRS: long-read sequencing; sr-NGS: short-read next-generation sequencing; STR: short tandem repeat; WES: whole exome sequencing; WGS: whole genome sequencing]