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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.

CLINICAL SIGNS

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 www.naadvocacy.org 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 amazon.com
  • 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



:: naadvocacy.org

naadvocacy.org 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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RESEARCH UPDATE
European Multidisciplinary Initiative on Neuroacanthocytosis

The European Multidisciplinary Initiative on Neuroacanthocytosis is the culmination of a seven-year project at the Advocacy to fund early-stage NA research, with the ultimate aim of attracting significant outside investment. The success of this "seed money" strategy came in early 2010: a group of Advocacy grant recipients launched the European Multidisciplinary Initiative on Neuroacanthocytosis (EMINA), a program which with other collaborators received a €650,000 European Union grant.

Copyright ydhsu / Daniel @ Flickr
This is an exciting time for us as the first status reports come in from EMINA researchers. Please note that the summaries below are interim progress reports only. The researchers are working with unpublished data that is to remain confidential, but if you would like a fuller report on the EMINA research, please contact Glenn Irvine.

NA reference centre located in Munich
An important bank of research material has been created.  Clinical data as well as over 300 related blood samples, treated to preserve their DNA in a long-term biobank, from patients suspected of having ChAc are now available.  Meanwhile pathological examination of tissue from 12 brains likely to be affected by ChAc has begun and results will be compared to the findings in Huntington’s disease to learn more about the nature of ChAc.  Muscle tissue from 10 patients is being examined and the organ specificity of chorein in human patients is being compared to the chorein mouse model reports. This material is available to other researchers on application to Prof. Adrian Danek.

Vesicle formation in NA
Collected blood samples are analyzed using images obtained by advanced microscopy techniques in order to investigate the cause of acanthocyte formation (the misshaped red blood cells associated with NA), and vesiculation (creation of small bodies that move substances within and out of cells) is investigated by the analysis of the protein and lipid organization of red blood cell membranes and vesicles. A new finding is that there is a relationship between band 3 organization and plasma vesicle concentration.

NA red cell membranes composition and the mechanism of vesicle formation in erythrocytes and acanthocytes of patients with various forms of NA
Biochemical analysis of blood samples from 16 patients with one of the NA diseases in Germany, Turkey and the UK of cell membranes showed differences in protein composition.  Differences in vesiculation activity were also identified between cells from NA patients and controls that are still being studied.


Develop Drosophila models for ChAc and HD l-2 in addition to the existing Drosophila PKAN model to identify underlying common mechanism of cell degeneration
The goal is to create models of ChAc and HD l-2 by removing from fruit flies the Vps13 or jp genes that missing in patients with ChAc and HDl-2.  The genes have been removed and studies of how this affects the fly are underway.

Clinical evaluation of NA patients
Focus is on 9 ChAc patients and one MLS patient who have been treated by deep brain stimulation. Data from patients is being collected together with videos that allow comparison of individuals’ movement problems.  This has already led to a publication describing a MLS patient with “head drop” and an article in preparation on feeding dystonia in MLS patients. There will also be a comparison of the movement problems of NA patients compared to Huntington’s disease patients.

Set up a diagnostic centre for ChAc located in Istanbul ITF
Families with multiple patients have been tested and have given blood samples that are of great value to other EMINA participants.


Additional research supported the Advocacy for Neuroacanthocytosis Patients

Purification and biochemical function of yeast Vps13 protein - University of Michigan
Supported by a grant from the Advocacy for Neuroacanthocytosis Patients

This is a study of the basic biochemistry of Vps13 protein (Vps13p), the yeast homolog of the chorea acanthocytosis disease protein, VPS13A, which is absent in ChAc patients.  We have reconstituted vesicular transport between the trans Golgi network and late endosome in a cell-free system using yeast extracts and have discovered that extracts from vps13 mutant strains are defective in this trafficking step and can be complemented by purified Vps13p.  We also confirmed that the small calmodulin-like calcium-binding protein Cdc31p interacts with Vps13p. 

The two aims of the grant are (i) to purify and characterize an active form of Vps13p and (ii) to determine the role of Cdc31p in Vps13p function.  Significant progress has been made on both aims. 

We have shown that cdc31 mutant extracts are also defective for TGN-PVC transport and that this defect can be complemented by adding purified Vps13p.  This result implies that Cdc31p is required for TGN-PVC transport and that the form of Vps13p that is active in TGN-PVC transport is a Vps13-Cdc31 complex.  Currently we are using deletion analysis to map sequences in Vps13p required for binding to Cdc31 and for interacting with late endosomal membranes.


In vitro modelling of Chorea-acanthocytosis (ChAc): Patient fibroblasts and their reprogrammed derivatives as human models of ChAc – Department of Neurology and Center for Regenerative Therapies (CRTD), Technical University of Dresden
Supported by a grant from the Advocacy for Neuroacanthocytosis Patients

The overall aim of our ongoing project is to establish an in vitro model of ChAc using skin fibroblast lines and reprogrammed fibroblasts (induced pluripotent stem (iPS) cells) from patients suffering from ChAc. Both cell types will be used as in vitro models to study basic mechanisms of the molecular pathophysiology of ChAc. In the last 6 months we characterized the fibroblast samples of ChAc patients. No differences were found in expression of antioxidant enzymes and mitochondrial biogenesis factors between ChAc patients and controls. However, we found signs of pronounced oxidative stress in fibroblast samples of ChAc patients. There were no differences in ATP production and lactate production. We recently identify severe secondary cell membrane disturbances within erythrocytes from ChAc patients. Interestingly, this is neither obvious in the neurons derived from ChAc-hiPS neurons nor in fibroblast cells suggesting different downstream targets of VPS13A gene in different cell types.

In the meantime we succeeded in deriving IPS cell lines from two patients. After having characterized them in terms of pluripotency, we will investigate the molecular pathophysiology and the molecular differences within striatal vs. other neuronal subtypes. This is of central interest since the above mentioned results from fibroblasts and erythrocytes points towards an organ specific pathophysiological role and thus therapeutic target of ChAc. Thus, we could prove the importance of the development of a human ChAc cell model, which however needs to be scaled up to reach the overall aim of developing a sufficient causal therapy for this disease.

 
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