Abnormal red cell structure and function in neuroacanthocytosis

BackgroundPanthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditaryneurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneousgroup of diseases is characterized by degeneration of neurons in the basalganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes,in the circulation.ObjectiveThe goal of our study is to elucidate the molecular mechanisms underlying this aberrant redcell morphology and the corresponding functional consequences. This could shed light onthe etiology of the neurodegeneration.MethodsWe performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemicaland functional analysis of the red cells of several patients with PKAN and, for thefirst time, of the red cells of their family members.ResultsWe show that the blood of patients with PKAN contains not only variable numbers ofacanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent andimmunoblot analyses suggest an altered membrane organization, rather than quantitativechanges in protein expression. Strikingly, these changes are not limited to the red bloodcells of PKAN patients, but are also present in the red cells of heterozygous carriers withoutneurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients’ cells, however, are more fragile,as observed in a spleen-mimicking device.ConclusionThese morphological, molecular and functional characteristics of red cells in patients withPKAN and their family members offer new tools for diagnosis and present a window into thepathophysiology of neuroacanthocytosis.