Following the identification of various causative genes for NBIA, and the recent development of animal models, some early, cautious, remarks can be made regarding a common underlying theme for NBIA pathogenesis. For all NBIA subtypes, with the exception of FAHN, studies in patient material or in animal models demonstrate a strong association with oxidative stress. This may be due to aberrant lipid homeostasis, iron homeostasis, mitochondrial functioning or a combination of the three. Further studies, additional animal models, identification of causative genes of the idiopathic forms of NBIA are required to fully understand the basic mechanisms of NBIA and to develop rational therapies.
Is iron simply a biomarker of NBIA disease or is it pathogenic? For most forms of NBIA, iron accumulation is secondary and its role in pathogenesis remains unclear. Almost certainly iron chelation will not prevent the primary neurodegenerative process. At the same time, massive amounts of intra- and extra-cellular iron are predicted to t be deleterious and are strongly suspected to contribute to pathogenesis. While iron chelation may have a role in experimental therapies for NBIA, efforts to overcome the primary defects remain the therapeutic goal.
Membrane dysfunction appears to offer a tantalizing hint for understanding the two core NA syndromes, ChAc and MLS. In both, a protein is absent from red cells and most likely also from neuronal membranes. In contrast, the acanthocytosis of PKAN is probably best understood on the basis of membrane lipid abnormalities. In any case, circulating erythrocytes offer the welcome possibility of a model system for NA and NBIA.
For future research, it is of interest that following the description of the McLeod antigen variant of red cells by blood banks, it took sixteen years before their exotic shapes were noticed (Wimer et al., 1977
). Acanthocytes should thus be assiduously sought in the newer NBIA and NA syndromes. Also, since the rare Kell null subjects so far have not been properly examined outside of the hematology clinic, we propose that they be studied in greater detail by neurologists in case there are subtle neurological findings related to Kell/Kx dysfunction. Finally, although MLS may increasingly be understood as a delayed variant of ChAc with slower evolution of the multi-organ changes (Chauveau et al.,. 2011
; Gantenbein et al., 2011
), it is of particular note that cardiomyopathy is not found in ChAc, given that the assumed membrane dysfunction of NA probably also affects muscle cells.
Acanthocytic deformation of red cells is an intriguing feature shared by many of the conditions discussed above, and may possibly provide an essential clue for the understanding of their pathophysiology. The acanthocytic protrusion of parts of the cell membrane appears to be the result of disorganized membrane-cytoskeleton interactions due to defective endosomal trafficking and sorting, autophagic flux and autolysosomal degradation in late stage erythropoiesis. The protrusions and thorns of acanthocytes could perhaps be viewed as an arrested state among a multitude of continuously changing states of membrane deformation, thus potentially providing insights into basic mechanisms of cell biology.