Red blood cell lipid distribution in the pathophysiology and laboratory evaluation of chorea-acanthocytosis and McLeod syndrome patients

Donatienne Tyteca ^1* Anne-Sophie Cloos ¹ Marine Ghodsi ¹ Amaury Stommen ¹ Steffen M Recktenwald ² Lars Kaestner ³ Adrian Danek ⁴ Adrian Spranger ⁵ Andreas Hermann ⁵ Kevin Peikert ⁵

• ¹ de Duve Institute, Faculté de pharmacie et des sciences biomédicales, Université catholique de Louvain, Brussels, Belgium
• ² Okinawa Institute of Science and Technology Graduate University, Okinawa, Okinawa, Japan
• ³ Saarland University, Saarbrücken, Saarland, Germany
• ⁴ Institute of Medical Psychology, Faculty of Medicine, Ludwig Maximilian University of Munich, Munich, Bavaria, Germany
• ⁵ University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany

The core neuroacanthocytosis syndromes, i.e. chorea-acanthocytosis/VPS13A disease (ChAc) and McLeod syndrome/XK disease (MLS), are respectively due to mutations in VPS13A and XK genes and share similar manifestations including the formation of acanthocytes. We previously showed by lipidomics of RBCs from ChAc patients slight lipid changes compared to healthy controls. We here evaluated the consequences for RBC morphology, deformability, cytoskeleton and membrane lipid transversal and lateral distribution in 5 patients with ChAc and 2 patients with MLS. Compared to healthy donors, the two cohorts showed a strong increase of abnormal RBCs including acanthocytes and spheroechinocytes, a decrease in projected surface area and deformability, and a rise in spectrin density. The abundance of cholesterol-enriched domains and the proportion of RBCs with ceramide-enriched patches were also increased while phosphatidylserine surface exposure was slightly decreased. In contrast, the abundance of sphingomyelin-enriched domains was poorly affected. At the individual level, patients showing the highest cholesterol-enriched domain abundance exhibited the highest number of RBCs with ceramide-enriched patches, compatible with RBC maturation defects, whereas patient RBCs exhibiting the highest spectrin membrane density showed the strongest loss of RBC area and the lowest abundance of sphingomyelin-enriched domains, consistent with RBC membrane alterations. Our study indicated that abnormal RBCs were associated with lipid distribution and cytoskeleton impairments, which appeared to result from both RBC maturation defects and membrane alterations. Moreover, the extent of lipid distribution alteration is well correlated with laboratory parameters typically altered in neuroacanthocytosis and could present an added value in neuroacanthocytosis syndrome evaluation.