Differential diagnosis of ataxia types

Autosomal recessive cerebellar ataxias (ARCAs) are rare and early-disabling neurodegenerative-movement disorders caused by dysfunction in the cerebellum. The most common form is Friedreich ataxia. A less common form is ataxia with oculomotor apraxia type 2 (AOA2), which is caused by mutations in the senataxin gene. This is a large gene, and sequencing it is a long and expensive undertaking; therefore, patient selection prior to sequencing is an important step.

An international team of researchers, including several from the Kingdom of Saudi Arabia, Sudan and Algeria, performed a retrospective analysis of clinical, laboratory, electrophysiological, imaging and molecular data from all patients who underwent sequencing of the senataxin gene between 2004 and 2008 owing to a combination of cerebellar ataxia with elevated α-fetoprotein (AFP) serum level.

They attempted to identify important clinical biological markers to determine better upfront which patients are most likely to have AOA2. Of the 125 patients tested, 90 were found to be AOA2 positive (AOA2+) and 35 were AOA2 negative (AOA2–). In the AOA2+ individuals, AFP levels were found to be significantly and more frequently higher. Peripheral neuropathy was more common in AOA2+ than AOA2– patients, as was strabismus and high foot arch (pes cavus). Other clinical signs such as cerebellar atrophy on magnetic-resonance imaging, oculomotor apraxia, head tremor, dyskinesia and dystonia were not found to be significantly different.

The researchers recommend that AFP is the most useful biomarker for AOA2, with a cut-off value of ~7 µg/L. Strabismus was also highly suggestive of AOA2, and lack of both peripheral neuropathy and cerebellar atrophy appears to exclude diagnosis of AOA2, as all patients in the cohort had at least one of the two signs. Using these criteria should help with clinical diagnosis of AOA2 and improve the chance of a positive genetic test.

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