Objective: To identify the genetic cause in patients with CANVAS recruited at the University Hospital of Schleswig-Holstein, Campus Lübeck.

Background: CANVAS is a late-onset neurological syndrome characterized by the combination of cerebellar ataxia, neuropathy and bilateral vestibular areflexia. The clinical diagnosis of CANVAS might be missed due to a limited awareness for vestibular areflexia and sensory pathology as the clues to the correct diagnosis. A homozygous, intronic pentanucleotide expansion has recently been identified as the underlying genetic cause of CANVAS.

Method: We included 82 individuals of whom 15 had “complete CANVAS” (triad of clinical signs), 7 with “incomplete CANVAS” (all three systems affected but incomplete), 46 patients with late-onset cerebellar ataxia of undetermined cause without specific information on sensory and vestibular function, and 14 healthy controls. We tested for the repeat expansion using a duplex PCR. Furthermore, a repeat-primed PCR was established. Sanger sequencing was used to ensure specificity of the assays.

Results: The homozygous pentanucleotide expansion was identified in 14/15 patients (93.3%) with “complete CANVAS”, in 1/7 (14.2%) with “incomplete CANVAS”, and in 3/46 (6.5%) of other ataxia patients but in none in any of the controls. The existence of the expanded repeat was validated by repeat-primed PCR.

Conclusion: A homozygous pentanucleotide repeat expansion is a highly frequent cause of CANVAS explaining the vast majority of cases. The presence of the repeat expansion also in “incomplete CANVAS” and unselected ataxia patients suggests that the diagnosis of CANVAS might often be clinically missed in patients who were not specifically tested for sensory and vestibular dysfunction. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-homozygous-pentanucleotide-repeat-expansion-in-cerebellar-ataxia-neuropathy-and-vestibular-areflexia-syndrome-canvas/