Objective: Follow up on patients with strong clinical evidence on VPS13A disease, despite normal chorein band expression in Western blot.

Background: VPS13A disease is a rare, autosomal recessively inherited neurodegenerative disorder caused by mutations in the VPS13A gene, coding for the chorein protein. Next to DNA studies, Western blot (WB) analysis of chorein is of great diagnostic value for all suspected cases, in particular when quick diagnosis is required or when genetic studies of the complex VPS13A gene are not easily available. Dobson-Stone et al. (2004) showed that the chorein band detected by WB of erythrocyte (red blood cell, RBC) membranes was absent or severely reduced in VPS13A disease patients, with already confirmed VPS13A mutations. Financially supported by the Advocacy for Neuroacanthocytosis Patients (www.naadvocacy.org) we were able to offer the chorein WB for free as of 2006. Up to now we have received more than 700 samples from patients with a clinical suspicion of chorea-acanthocytosis.

Method: Western blot was carried out using a polyclonal antiserum (anti-chor1) against the N-terminal region of chorein (Dobson-Stone et al. 2004).

Results: In 194 cases, we confirmed a diagnosis of VPS13A disease based on the absence or clearly reduced levels of RBC membrane chorein. Interestingly, a number of patients showing normal chorein levels presented with highly suggestive clinical features of VPS13A disease; a genetic follow-up with whole-generation-sequencing platforms has been started in a number of cases and, so far, pathogenic mutations in VPS13A have been detected in six of them. These mutations include splice-site, frameshift and nonsense changes.

Conclusion: Our observations confirm that the chorein WB has less than 100% sensitivity for the diagnosis of VPS13A disease. Thus, they stress the need to follow up on patients with clinical features highly suggestive of VPS13A disease even if chorein WB appears normal. These observations may relate to properties of the antibody used. Studying these cases can provide valuable insight about functional domains and stability of chorein.
A part of the above mentioned results in a previous form has been presented at the 10th International Meeting on Neuroacanthocytosis Syndromes, 11.March 2021.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/normal-chorein-protein-signal-on-western-blot-despite-vps13a-mutations-in-vps13a-disease/