Abnormal red cell structure and function in neuroacanthocytosis.
BACKGROUND
Panthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation.


OBJECTIVE
The goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration.


METHODS
We performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members.


RESULTS
We show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological 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.


CONCLUSIONS
These morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis.
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Judith C A
JC
Cluitmans
Department of Medicine, University of Verona-AOUI-Verona, Policlinico GB Rossi, P.le L Scuro, 10, 37134 Verona, Italy.
Carlo
C
Tomelleri
Division of Child Neurology, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Zuhal
Z
Yapici
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Sip
S
Dinkla
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Petra
P
Bovee-Geurts
Department of Physical Organic Chemistry, Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
Venkatachalam
V
Chokkalingam
Department of Medicine, University of Verona-AOUI-Verona, Policlinico GB Rossi, P.le L Scuro, 10, 37134 Verona, Italy.
Lucia
L
De Franceschi
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Roland
R
Brock
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Giel J G C M
GJ
Bosman
D000050:Acanthocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000328:Adult; D000368:Aged; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D048430:Cell Shape; D002648:Child; D004906:Erythrocyte Count; D004910:Erythrocyte Membrane / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D054546:Neuroacanthocytosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009996:Osmotic Fragility; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010375:Pedigree; D013049:Spectrin / Q000235:genetics / Q000378:metabolism
D001457:Anion Exchange Protein 1, Erythrocyte; D008565:Membrane Proteins; C454201:SLC4A1 protein, human; C036860:STOM protein, human; D013049:Spectrin