Comprehensive Ataxia Testing (Reflex testing option)

Ataxias, hereditary or sporadic, represent a clinically and genetically complex group of neurological disorders that are characterized by uncoordinated body movements and may present with gait abnormalities, dysarthria, apraxia, dysphagia and other pyramidal and extrapyramidal signs.  The ataxia symptom can be isolated or part of a multisystemic neurological disorder, presenting at ages ranging from infancy to adulthood, and can be dominant, recessive, X-linked or mitochondrial. Genetic testing for hereditary ataxias remains challenging mostly due to the significant clinical overlap and genetic heterogeneity with more than 500 genes reported to be associated with ataxia or ataxia-like presentation. Targeted exome sequencing is regarded as a powerful diagnostic tool for heterogeneous neurological disorders such as ataxia but limited in its ability to detect repeat expansions which are estimated to account for over 50% of dominant hereditary ataxias. The UCGSL provides a comprehensive testing approach for the diagnosis of neurodegenerative disorders that includes a targeted exome sequencing analysis of a predefined, and continually updated set of 500+ genes and a repeat expansion panel consisting of 13 genes. The ataxia exome involves analysis of exome sequencing data in a predefined set of genes associated with ataxia and ataxia-related disorders. The most common repeat expansion disorders include the autosomal dominant spinocerebellar ataxias (SCAs) and the autosomal recessive Friedreich ataxia. Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by a premutation in the FMR1 gene, is the most common X-linked cause of cerebellar ataxia. Recently, a biallelic intronic expansion in the RFC1 gene has recently been identified in the majority of patients with CANVAS (Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome) and in a proportion of late onset ataxia patients. An intronic GAA expansion in the FGF14 gene has recently been identified in several individuals with previously unexplained late-onset ataxia (PMID: 36516086, 36493768). The identification of this intronic expansion has led to the discovery of a new form of autosomal dominant hereditary ataxia, spinocerebellar ataxia type 27B (SCA27B). The reflex testing option starts with the repeat expansion panel followed by the ataxia exome if negative.