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.
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.
Research Update This issue we look at 'The role of XK protein in Erythrocyte ion transport function', 'Vps13A regulation of phosphatidy linositolphosphate pools in mammalian cells', 'Functional analyses of ion channels in Chorea-Acanthocytosis (ChAc) patient-derived induced pluripotent stem cells and differentiated neurons in vitro' and 'In vitro modelling of Chorea-acanthocytosis (ChAc): Patient fibroblasts and their reprogrammed derivatives as human models of ChAc'.
Progress report “The role of XK protein in Erythrocyte ion transport function. Alicia Rivera PhD at Children’s Hospital, Harvard Medical School, Boston, USA
Alicia Rivera PhD at Children’s Hospital, Harvard Medical School, Boston, USA. For more photos from Issue 19 of NA News visit our Facebook Page.
This study will test the molecular mechanisms that are important in the development of acanthocytic red cells in patients with McLeod Neuroacanthocytosis Syndrome (MLS). This is a rare genetic disease, which is caused by an error in a single DNA gene, which is called the XK gene (XK). Lack of knowledge on what the XK protein does in the body has been the major difficulty in management of the disease. Therefore, the goal of this project is to identify and characterize the physiological role of XK protein in erythrocytes. Our latest report in Blood Cell, Molecules and Diseases (Rivera et al, 2012) showed strong evidence of previously un-described alterations in erythrocyte cellular magnesium ion and potassium ion homeostasis in Xk knockout mice when compared to the wild-type.
We want to see whether this alteration can be also seen in human McLeod red cells before affected individuals develop MLS. Unfortunately, progress in the project has been hampered by the lack of potential and suitable candidates for the project. We are currently seeking patients who have been diagnosed with lack of Kx antigen, McLeod syndrome and taking no medication for neurological, or other disorders such as benzodiazepines, anticonvulsants, anti-hypertensive or other cardiac medications, and antidepressants. We would like to recruit young McLeod individuals who have not developed symptoms, yet, and are not on medications to accomplish our goal supported by a grant from the Advocacy for the Neuroacanthocytosis patients.
Publication:
Ablation of the Kell/Xk complex alters divalent cation homeostasis. Rivera A. Kam SY, Ho M, Romero JR and Lee, S. Blood Cells and Molecular Diseases, 2012 Oct 30 [Epub ahead of print]
Family/Patients:
If you have been told by your doctor that you have McLeod syndrome, or that you lack the Kx antigen in your red cells, you may qualify for this research study. It is important that you are not taking any medication as this could interfere with the studies of red cells. We are only approved to recruit adults over the age of 21 years. If you qualify, participation would involve 2 visits to your doctor to give a medical and family history and to have blood samples taken. There are no medications involved. As part of the study you will be asked to contact close family members to see if they would also like to participate. You will not receive any personal health benefits as a result of your participation in this research study. However, the results will allow us to better comprehend McLeod syndrome and thus benefit patients in the future.
For Physicians:
There are no medications involved. Researchers will isolate DNA from one blood sample, so that they can confirm the lack of Kx antigen. The study will assess cation transport across intact red blood cells and estimate how this critical red cell function is affected by the absence of XK protein.
If you would like to receive additional information about participating in this important Institutional Review Board approved research study, please contact Dr. Alicia Rivera, Principal Investigator, or Dr. Ruth Walker, patient recruiter by email: alicia.rivera@childrens.harvard.edu or ruth.walker@mssm.edu . (The family of Mark Willard supported by the Advocacy made this grant directly.)
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Vps13A regulation of phosphatidy linositolphosphate pools in mammalian cells Aaron Neiman
In the budding yeast Saccharomyces cerevisiae, the Vps13 protein has multiple functions. It is required for transport of other proteins to the vacuole during vegetative growth and, separately, for assembly of intracellular membranes during sporulation. We have discovered that during membrane assembly Vps13 regulates the levels of specific lipids within the growing membrane. Lowered levels of these specific lipids lead to the membrane abnormalities seen in vps13 mutant cells. With funding from the Advocacy, we are testing the hypothesis that the Vps13 ortholog, Chorein, similarly regulates specific lipids in mammalian cells. If this hypothesis is correct it may provide clues as to the molecular basis of the phenotypes seen in patients with Chorea acanthocytosis and suggest strategies for the treatment of the disease symptoms.
Diagnostic report Benedikt Bader, Munich
Benedikt Bader. For more photos from Issue 19 of NA News visit our Facebook Page.
In total, we analysed 76 patients’ samples in 2011 and 23 patients in the first 6 months of 2012 in the diagnostic Western blot assay. In total, we were able to identify 22 patients suffering of chorea-acanthocytosis in 2011 and 6 in the first half of 2012. Samples have been sent in mostly from Germany, the UK and Turkey but also from Australia, Bulgaria, India, Iran, Israel, Canada, South Korea, Austria, Poland, Sweden, Switzerland and the US. Although numbers are decreasing recently, 29 new patients could be identified, some of whom joined the Advocacy for Neuroacanthocytosis.
New manuscripts to publish scientific data
Two manuscripts are ready for publication. The first investigates the presence of chorein in non-brain organs and reports a preference for mesoderm organs such as brain, blood, muscle and nerve. Mesoderm is a kind of tissue that develops during the embryonal state and differentiates in skeletal muscle, blood and blood vessels, spleen, kidneys and a few others. This explains that pathology besides brain will affect e.g. muscles, nerves and blood.
We then analysed various samples of muscle tissue that was acquired over the previous years from physicians all around the world. It appears that the pathology observed in muscle, like muscle weakness or muscle atrophy, is mostly due to the affection of nerval tissue.
Our ongoing project will analyse brain tissue and details of the pathology that occurs in human brain tissue, following the generous donation of tissue by 10 patients who agreed to offer their organs to us. Results are still pending but will presumingly be available in the first half of 2013. Thus, the Munich EMINA goals will be availbe upon the completion of tthe EMINA project.
Dr. Antonio Velayos Baeza, The Wellcome Centre for Human Genetics
Current research project on NA research at Oxford Dr. Antonio Velayos-Baeza Wellcome Trust Centre for Human Genetics, University of Oxford, UK
I have recently been awarded a research grant from the Advocacy for Neuroacanthocytosis Patients to continue our work in Oxford on the functional characterisation of chorein, the protein encoded by gene VPS13A, altered in patients with Chorea-Acanthocytosis (ChAc). This has allowed the appointment of a new Research Assistant with a 50% dedication to this project, Luiz Guidi, starting in October 2012. Luiz is an MSc Neurosciences graduate from the University of Oxford, and we both attended the recent 2nd NA/NBIA symposium in Ede, The Netherlands, a perfect opportunity for him to get to know many of our funders, collaborators, and the different research focusses in this field.
We have just initiated our work in this project. We will conduct a number of experiments directed to complete our basic characterisation of chorein at the cellular level, and will try to find answers to some questions such as where inside the cell this protein is found, or what happens to chorein when changes similar to some of those found in ChAc patients are introduced. We also intend to analyse the putative application of some antibodies to further improve the chorein test currently used as a key element in the diagnosis of ChAc.
Functional analyses of ion channels in Chorea-Acanthocytosis (ChAc) patient-derived induced pluripotent stem cells and differentiated neurons in vitro F. Wegner, N. Stanslowsky, A. Hermann, A. Storch
The aim of this research project is to gain insight into the functional pathomechanisms of Chorea-acanthocytosis (ChAc). Recently, we established a human in vitro model of ChAc by genetic transformation of patient skin fibroblasts allowing the generation of induced pluripotent stem cells (iPSC). In this project, two ChAc patient-derived and one healthy control iPSC line are differentiated into neurons to study their ion channel function and synaptic activity.
For derivation of striatal medium spiny GABAergic neurons that are the main target of neurodegeneration in ChAc we have established an efficient differentiation protocol for iPSC based on the research with embryonic stem cells (Ma et al. 2012, Cell Stem Cell). iPSC colonies are cultured as embryoid bodies in suspension to induce differentiation. After attachment to cell culture plates the embryoid bodies start to form neural tube like rosettes as a sign for an early neuronal stage. After further differentiation progenitor clusters are disrupted into single cells and replated onto culture dishes. Valproic acid is added to generate GABAergic progenitors, followed by a set of cytokines to produce a large population of mature striatal medium spiny GABAergic neurons for functional analyses. We will compare the functional data of disease-specific and healthy control neurons in order to shed light on the functional pathophysiology and hopefully identify a potential therapeutic target to treat ChAc.
In vitro modelling of Chorea-acanthocytosis (ChAc): Patient fibroblasts and their reprogrammed derivatives as human models of ChAc A. Storch
The overall aim of our ongoing project is to establish an in vitro model of ChAc using nerve and blood cells from reprogrammed fibroblasts (induced pluripotent stem (iPS) cells) from patients suffering from ChAc. After having established a general neuronal differentiation of ChAc-iPS lines, the last months were used to develop and optimize differentiation protocols for high yield of erythrocytes as well as striatal nerve cells (medium spiny neurons) from ChAc-iPS.
Interestingly, erythrocyte from patient iPS cells showed spontaneously an acanthycytic morphology. These will now be used to investigate possible targets ameliorating the red blood cell phenotype.
We did not yet observe a phenotype in the patient derived neurons. This may have different explanations: our differentiation protocol select healthy neurons and possible disease phenotypes are missed due to cell death prior to analysis. Alternatively, since ChAc is not a developmental disease, we may have to age the neurons in the dish to see neurodegeneration in vitro. This will be done in the next months using different stressors known to influence mechanisms of cell aging.
Thus we now have the cells of interest in hand to further analyze the neuronal as well as erythrocytes pathophysiology.
