"Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pank2 is the only pantothenate kinase isoform that is localized to mitochondria playing a non-redundant role in neuronal lipid metabolism.
Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations.
In this study, we analyzed acanthocytosis of a cohort of PKAN patients from Cabral (Dominican Republic) that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wildtype with respect to this mutation. Molecular analyses of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme resulting in protein instability rather than total enzymatic inactivity. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (<10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis.
Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a model for PKAN associated acanthocytosis that accounts for the variability in the occurrence of acanthocytic cells" (SCHIESSL-WEYER et al., 2015).