Ataxia with Oculomotor Apraxia Panel

Ataxia with oculomotor apraxia (AOA) is an early-onset, autosomal recessive cerebellar ataxia characterized by oculomotor apraxia (inability to coordinate eye movements), peripheral neuropathy, and hypoalbuminemia. Depending on the mutated gene, AOA has been categorized into different types. Phenotypically, these forms share several similarities (Le Ber et al. 2005; Bohlega et al. 2011), which suggests that testing all the genes associated with this phenotype may be a good approach.

AOA is genetically heterogeneous and is an autosomal recessive disorder. It is caused by pathogenic variants in the APTX, SETX and PIK3R5 genes (Ito et al. 2005).

AOA type 1 (AOA1) is due to pathogenic variants in APTX. APTX encodes the aprataxin protein, which is involved in DNA single-strand-break repair (SSBR) (Mosesso et al. 2005; Hirano et al. 2007). It has been reported that loss of aprataxin function leads to accumulation of SSBs, which results in human neurodegenerative disorders such as AOA1 (Tada et al. 2010).

AOA type 2 (AOA2) is due to pathogenic variants in SETX. SETX encodes the senataxin protein, which is also involved in the DNA repair pathway (Moreira et al. 2004).

AOA type 3 (AOA3) is due to pathogenic variants in PIK3R5, which encodes a p101 regulatory subunit that interacts with phosphoinositide-3-kinase (PI3K). PI3Ks are involved in various signal transduction pathways that regulate cell survival and growth, metabolism, immune, and cardiac functions (Al Tassan et al. 2011).

So far, about 30 causative variants in APTX (missense, nonsense, splicing, small deletions, small insertions and gross deletions); over 150 pathogenic variants in SETX (missense, nonsense, splicing, small deletions, small insertions, indels, gross deletions/duplications and complex genomic rearrangements) and one missense causative variant in PIK3R5 have been reported that are associated with AOA (Human Gene Mutation Database).

See individual gene test descriptions for more information on molecular biology of gene products.

Castellotti et al. identified APTX pathogenic variants in 6% of their ataxic patients (13 out of 204) (Castellotti et al. 2011). A mutation screening 22 in Italian patients from 21 families detected SETX pathogenic variants in 13 patients (12 families) (57%), and APTX pathogenic variants in 3 patients (Nanetti et al. 2013). Clinical sensitivity for the PIK3R5 gene is difficult to estimate due to the limited number of cases.

Currently, only SETX aCGH testing is available. Gross deletions are relatively common in this gene (Nanetti et al. 2013).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).