Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Is postoperative encephalopathy with choreoathetosis an acquired form of neuroacanthocytosis?

Postoperative encephalopathy with choreoathetosis ("postpump chorea") is a rare complication of open-heart surgery and, in particular, the employment of a cardiopulmonary bypass pump. It almost exclusively occurs in young children. While risk factors and the underlying histopathology have been identified, the pathogenesis of postpump chorea, crucially, remains largely unknown. Transient cerebral hypoperfusion associated with cardiopulmonary bypass is considered a likely candidate mechanism, but the evidence is insufficient and inconclusive. It is hypothesized in this article, that postpump chorea may be caused by mechanical trauma to red blood cells and resulting acanthocytosis. These dysfunctional erythrocytes could then lead to damage to the globus pallidus and disease development akin to that presumed in neuroacanthocytosis. In patients with neuroacanthocytosis an association between acanthocytosis and basal ganglia pathology has been suggested. To test the mechanism hypothesized here, the effects of cardiopulmonary bypass on erythrocyte morphology and function could be systematically tested in children undergoing cardiac surgery. Ideally, the extent of erythrocyte damage could be correlated with the risk of developing postpump chorea. Finally, if the proposed hypothesis is supported by empirical findings, efforts to reduce blood cell damage during extracorporeal circulation in children might prevent this devastating complication.