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:: How to recognise Neurocanthocytosis

The first signs of the diseases in the neuroacanthocytosis (NA) group are subtle and easily overlooked. Initial symptoms, which often occur in the person’s mid 20’s, may include grunts or tic noises made unconsciously in the throat, progressing to drooling and problems in controlling the tongue from ejecting food. Involuntary biting of the tongue, lips and/or cheeks may follow.

At the beginning there can be a general, slight physical awkwardness. Things on a shelf are knocked off for no apparent reason. Difficulty with walking and balance can also be early symptoms. Problems controlling trunk, leg and arm movements are often barely noticeable at the beginning, but become increasingly difficult as the disease progresses. Several patients find it difficult to sleep at night and others report fatigue and weakness.

Personality change may also be an early indication. The carefree young adult becomes obsessive-compulsive and uncharacteristically forgetful or just loses confidence or drive. Fainting or epileptic seizures may also occur. Mood changes may happen and a person often becomes isolated, in part out of embarrassment.

There are several reports of the problems beginning after a traumatic event including physical attack, unexpected failure of an exam and birth of a child.


A defining symptom that is not apparent is the spiky red blood cells, or acanthocytes, from which the NA disease group takes its name. These unusual blood cells can be observed with a microscope in some circumstances. Still more difficult to observe are the alterations or mutations in patients’ genes. Each of the NA group diseases has a different genetic characteristic that can be determined only by blood tests.

A person showing some of this pattern of symptoms should see a neurologist. Clinicians and patients can also visit for links to further scientific reports. Full details are also available on the free blood testing service offered by the Advocacy for Neuroacanthocytosis Patients, aimed at helping determine a definitive diagnosis for NA.

:: Useful NA Resources

  • Neuroacanthocytosis Syndromes II, published December 2007, the book provides a profound insight into recent developments within the field of neuroacanthocytosis syndromes. Edited by Ruth H. Walker, Shinji Saiki and Adrian Danek. Available at
  • A Western blot test for the presence of chorein in the membranes of red blood cells can be offered free of charge due to support of the Advocacy for Neuroacanthocytosis Patients'. Download instructions on the blood sampling and specimen shipment as a PDF or get more information on the method at PubMed
  • The entry for chorea acanthocytosis in GeneReviews is the most complete, readily available report on ChAc. Published by the University of Washington with the support of the National Institutes of Health
  • A dedicated Patient & Families Support Group at Yahoo Groups offers patients and families information, advice, support or just an understanding ear
  • Visit PubMed for access to NA research in English from the Medline database.
  • Search Google for the latest on NA
  • Visit the NA page on WeMove, the Movement Disorder Societies charitable and educational associate

:: is the website of the The Institute for Neuroacanthocytosis. It is the Advocacy's international centre for supporting patients and promoting clinical and basic research. The website provides access to resources found on the website.

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 Stem cells - copyright Joseph Elsbernd @ Flickr

The role of XK protein in Erythrocyte ion Transport Function.

Alicia Rivera, MS, PhD, Boston Children’s Hospital / Harvard Medical School, Boston, USA

The McLeod syndrome is a rare genetic disease caused by an error in the XK gene (XK) in the X-Chromosome. The specific goals of this project are to identify and characterize the physiological and functional role of XK proteins in erythrocytes. We have recently reported (Blood Cell, Molecules and Diseases, Rivera et al, 2012) strong evidence of a previously un-described alteration in erythrocyte cellular magnesium and potassium ion homeostasis in cells from Xk knockout mice when compared to wild-type mice. We have now significantly expanded on these observations in rodents. Our results indicate that red cells from a young patient with XK mutation but no MLS presentation show an 18% increase in intracellular K+ (245.3 to 288.5 mmol/Kg Hb) and Mg2+ (5.6 to 7.5 mmol/Kg Hb) that was associated with lower total calcium levels (1.1 to 0.3 mmol/Kg Hb) when compared to erythrocytes from otherwise healthy subject as determined by atomic absorption spectrophotometry.

These results suggest the existence of alterations in cation transporters in the cells from this patient. Indeed and consistent with this hypothesis, a more detailed investigation revealed that Na+ independent Mg2+ permeability in these red cells was likewise altered (2.0 to 0.6 mmol/1013 cell x h). In addition, we observed that the Na/Mg exchanger was significantly altered in cells from this young patient when compared to the control. Furthermore, we also evaluated K+ transport mediated by the Gardos channel (Ca2+ stimulated K flux) in the erythrocytes from this patient and observed significantly increased activity when compared to cells from healthy subject (18 to 26.8 mmol/1013 cell x h). These alterations in the Na/Mg exchanger and the Gardos channel are consistent with what we observed in the mice that lacked the Xk gene. Na+ transport was also evaluated but no significant differences were found in the Na pump, Na/K/2Cl cotransport or Na/H exchanger activity. Small changes, albeit significant, in mean cellular volume or red cell distribution width were observed in this patient.

However, more patient samples should be studied to confirm these observations. These results provide two important contributions to the field, 1) they show strong evidence suggesting that Xk deletion leads to changes in the erythrocyte cation homeostasis and 2) they strongly implicated Xk protein as a novel transporter and regulator of cellular magnesium and potassium ions; alterations that might play critical roles in the development of acanthocytic red cells in patients MLS. Thus our results are very promising and bring novel insight on potential mechanisms that may in part explain the development of acanthocytic erythrocytes in patients with MLS.

We thank Prof. Dr. Hans H. Jung from University Hospital in Zürich for his kind collaboration in providing us with the first sample. Another potential young MLS candidate from the Zürich group has been located and we are waiting for patient availability. One of these patients who is categorized as asymptomatic McLeod has a E327K missense mutation in XK gene product will be included in this study. We found two additional asymptomatic McLeod brothers who have this mutation in NY area.  We would like to include these McLeods patients in this study.  Thus, these asymptomatic subjects are very valuable to compare the results with McLeod with MLS. Including these McLeods in the study may give us additional valuable information in finding the physiological function of XK (and Kell).  

We are currently seeking patients who have been diagnosed with absence of Kx antigen, McLeod syndrome, that are not on any medication for neurological or other disorders and are not taking benzodiazepines, anticonvulsants, anti-hypertensive or other cardiac medications or antidepressants. Consequently we would like to recruit young McLeod individuals who have not developed symptoms.

Work in progress

Functional analyses of ion channels in Chorea-Acanthocytosis (ChAc) patient-derived induced pluripotent stem cells and differentiated neurons in vitro.

Florian Wegner, University of Hannover Medical School, Hannover, Germany

We are trying to understand the mechanism underlying neuronal degeneration in ChAc to develop neuroprotective treatment strategies. We established a model system of ChAc using the induced pluripotent stem cell (iPSC)-technology. iPSCs are immortalized, self renewing cells which were generated from skin cells of two ChAc patients and two healthy controls by genetic modification. Those iPSCs were differentiated into medium spiny neurons predominantly affected in ChAc. By comparing the neuronal properties of cells from ChAc patients to those of healthy controls altered ion currents in ChAc neurons were recorded, which point towards a pathological excitability that is believed to account for neuronal death in ChAc. We tried to ‘rescue’ the observed phenotype by treating the cells with the sodium channel blocking drug riluzole, which is already approved for treatment of other neurological diseases like amyotrophic lateral sclerosis. Alternatively, we followed the evidence obtained from erythrocytes of ChAc patients suggesting a causal relation of the observed excitability in ChAc neurons with a destabilized actin-cytoskeleton. Therefore, we investigated the effects of the actin stabilizer phallacidin as an actin-stabilizing agent Another starting point arose from the observation of elevated Lyn kinase activity and increased protein phosphorylation in ChAc erythrocytes. Assuming exalted protein phosphorylation also in ChAc neurons, we explored the impact of the kinase inhibitor PP2 on our cells. Future studies will be conducted to confirm our preliminary results by using more iPSC lines and in order to get a more detailed insight into the pathomechanism underlying ChAc.

An excellent review of neuroacanthocytosis including chorea-acanthocytosis, McLeod syndrome, Huntington’s-disease-like 2 and PKAN is available free on-line. This is a service of the  National Institute for Biological Information that is associated with the American National Institutes of Health.

Research project on ChAc “Study of the basic features and the role of chorein in human cell line models”, focussing on the features and role of chorein in mammalian cells.
Dr. Antonio Velayos-Baeza, Wellcome Trust Centre for Human Genetics, University of Oxford, UK

Here I present a report of our work during this first year (October 2012 to September 2013).

A detailed analysis of the sub-cellular localisation of chorein is among the main goals of this project, together with the study of the effect that pathogenic mutations predicted to cause small changes in this protein have in such localisation, as well as in the biochemical features and/or stability of chorein. For this purpose, it is necessary to have a proper record of the described ChAc pathogenic mutations. I have been maintaining such a record starting with all the mutations described by our past work on the genetics of ChAc in Oxford and updated with mutations reported by different research groups in scientific journals or in international meetings, or by personal communications.

These mutations are normally described just at the DNA level, but their effects at the mRNA or the protein levels are only known for a small proportion of them, and deducing such effects without empirical data is not always a straightforward task. The mutations interesting for our study are missense mutation (leading to substitution of a single amino acid in the protein), small duplications or deletions not changing the reading frame, splicing site mutations leading to exon skipping without change in reading frame, or stop codons close to the 3’end of the gene which would result in a mutant protein lacking a relatively short number of residues at the C-terminus of chorein. If possible, when information relevant to the effect of these mutations at mRNA and protein levels are not known, we try to get samples from patients carrying them. At this point we largely benefit from our close collaboration with Prof. Adrian Danek in Munich, having access to information about the effect of many of these mutations on the expression of chorein, as well as to contact details for patients and their clinicians.

A particularly interesting example of this is the analysis of mutations in ChAc patients with a very clear phenotype but with (seemingly) normal levels of chorein (as detected by western blotting on the “chorein test”). A few of such patients are known and at least 3 different mutations would fit in this category. We have managed to obtain from some of these patients new blood samples that we are currently using to study these mutations. At the same time, we are introducing these changes in our plasmids for over-expression in mammalian cells so their effect in sub-cellular localisation can be compared with the normal full-length protein, and will soon have a complete collection of “mutant plasmids” available.

Another specific point that we have addressed during this time is the possible use of some monoclonal antibodies against the C-terminus of chorein that we obtain during our previous project funded by the Advocacy for Neuroacanthocytosis Patients. We have confirmed we can detect the normal, non-modified chorein with at least one of these antibodies, although the concentration at the moment is very low, which makes it difficult to be used to detect endogenous protein. We are at the moment attempting the purification of this antibody from large amounts of culture medium so we can develop the assays necessary for its use in chorein tests and other applications on ChAc research.

Last year we started a collaboration project with the group of Dr. Pablo Mir, in Spain, as they were performing a neuromuscular study on several ChAc patients. This is an aspect in ChAc research that has not been properly studied, and where some reports involving “ChAc dominant cases”, which now we know are not such, have introduced some degree of confusion. We participated by carrying out the mutation screening of those patients included in the study and molecular detection of chorein by Western blotting using muscle biopsies. In connexion with this project, where initially 4 suspected ChAc patients from Spain were studied, we undertook a more exhaustive analysis of mutations present in ChAc patients from Spanish origin, making use of our collaboration with Prof. Adrian Danek in order to contact the relevant clinicians. A total of around 20 independent ChAc suspected cases are currently known, some of which had previously been screened for mutations, confirming 5 of them. Our analyses have detected 9 more positive cases and established a list of currently 12 different mutations in Spanish ChAc patients, including examples of new types of mutations not described before. This work is almost complete, and we expect the results to be published in two reports next year.

We currently maintain a number of collaborations with other researchers on this field, in some cases directly related to our own main research project as described above, although this is not always the case. However, in all instances, these collaborations are important to advance in a number of aspects on ChAc research, and I am keen to participate acknowledging that this is one of the main aims of the Advocacy for Neuroacanthocytosis Patients. Among these collaborations, the main ones are with groups participating in the EMINA project. Thus, a number of plasmids that I generated here in Oxford are now used by the groups of Drs. Ulrich Salzer, Mario Mairhofer, Andreas Hermann or Florian Lang. Additionally I have specifically developed several plasmids for expression of human chorein in fly as collaboration with the group of Prof. Ody Sibon in The Netherlands. These constructs will be used to analyse if human VPS13A cDNA can complement the effects of disruption of the fly homologous gene in the models obtained by Prof. Sibon’s group.

Analysis of Lyn Pathway on Target Cells from Chorea-Acanthocytosis and Development of New mouse Model for Chorea-Acanthocytosis
Lucia De Franceschi, MD, Dept of Medicine, Section of Internal Medicine, Policlinico GB Rossi, University of Verona, Italy

Projects Results

Aim 1. Analysis of Lyn kinases signaling network: regulation and identification of new Lyn related pathways in erythroid cells from NA patients. Task 1.1. We have previously have shown that Lyn, a Src family kinase, is abnormally activated in red cell membrane from patients with chorea-acanthocytosis (ChAc) (De Franceschi Let al Blood 2011). This is associated with weakening of protein-protein interactions between the integral membrane protein band 3 and the 4.1-adducin multiprolein complex bridging the membrane to the cytoskeleton. Recently, Ingley et al. reported that mouse genetically over-expressing Lyn show acanthocytes in the peripheral circulation and perturbation of erythropoiesis (Slavova-Azmanova NS et al. Blood 2013). To evaluate the ratio between activated Lyn (Lyn 396) and inactive Lyn (507), we immunoprecipitated total total Lyn from the red cell membrane of ChAc and control red cell membrane and revealed with specific antibody against either Lyn 396 or Lyn 507. As shown in Fig. 1 Lyn396 was the most abundant specie in ChAc red cell membrane compared to controls. Lyn 507 was almost undetectable in both groups. (To read the full report and view related figures, please download the PDF)

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