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
We are pleased to present research updates from investigators supported by the Advocacy. The Scientific Review Panel led by Professor Roger Albin at the University of Michigan collected and carefully considered evaluations from experts in each specific scientific area and recommended supporting these excellent proposals. The Advocacy supporters joined in raising most of the money needed and the additional financial resources for all these projects.
Our ability to continue funding research is reliant in large part on the generosity of our supporters, and the annual Big Give coming this December will be an important opportunity for us to raise research funds.
Evaluation of neuroprotective drugs in Chorea-Acanthocytosis (ChAc) patient-derived induced pluripotent stem cells and differentiated neurons in vitro from Florian Wegner and Alexander Storch respectively of the University of Hannover Medical School and Dresden Technical University.
The aims of this research project are to gain insight into the functional pathomechanisms of Chorea-Acanthocytosis (ChAc) and to test potential neuroprotective drugs in a human cell model of ChAc, an autosomal-recessive neurodegenerative disease of young adults manifesting in a hyperkinetic movement disorder and other severe neurological symptoms as well as in misshaped red blood cells.
This disease is caused by mutations in the VPS13A gene leading to a loss of the largely unknown function of the protein Chorein. Recently, we established a human cell model of ChAc using reprogrammed skin cells (fibroblasts) from ChAc patients. The genetic transformation of easily accessible ChAc patient cells allowed the generation of disease-specific induced pluripotent stem cells (iPSC) which behave similarly to embryonic stem cells without raising ethical concerns.
In a recent functional study we showed that iPSC-derived neurons from ChAc patients displayed significantly different ion channel properties (increased sodium channel amplitudes, action potential firing and synaptic activity) than healthy controls, which could represent a relevant therapeutic target to treat ChAc.
In this study, we want to validate our previous findings by analyzing 2 additional ChAc-iPSC and control cell lines and then evaluate the impact of potentially neuroprotective drugs like blockers of voltage-gated sodium channels, which are particularly important for the generation and conductance of action potentials in neurons. Each substance will be added to the iPSC derived from ChAc patients and effects will be compared to untreated ChAc-iPSC and healthy control cultures during neuronal maturation. The functional analyses of ion channels as well as toxicological tests of treated and untreated ChAc neurons will determine the degree of drug-induced neuroprotection in this human cell model. This study shall shed light on the functional pathophysiology of ChAc neurons with the future goal to render an effective neuroprotective therapy.
Continuation of Study of the basic features and the role of chorein in human cell line models Dr. Antonio Velayos-Baeza, Wellcome Trust Centre for Human Genetics, University of Oxford, UK
The main goal of this project is to obtain a good characterisation of the basic features of chorein, the protein altered in Chorea-Acanthocytosis (ChAc). To achieve this goal we will carry out a number of experiments aimed to find out where this and other similar proteins (the human VPS13 proteins) localise in the cell as well as to study other properties (biochemical features) that can give us important information. We will investigate if these VPS13 proteins are involved in phagocytosis and/or autophagy (cellular mechanisms for “eating” external particles or internal cell components, respectively). We will also analyse the effects that some particular mutations found in ChAc patients,(which are predicted to cause only small changes in chorein) have in the localisation, biochemical features and/or stability of this protein. We will also investigate the effects of absence/knockdown of endogenous chorein at the sub-cellular level. Experiments will be performed with commonly used mammalian cell lines and, in some cases, also cells directly obtained from ChAc patients.
The work required for this research plan will continue previous work carried out in the last few years by our group in Oxford. Thus, we already have an important number of tools and data available relative to chorein characterisation which are valuable assets for the success of this research project.
We expect to gain new insight in several areas of interest for the understanding of the role(s) of chorein which can then be used by the research community to address similar or new questions in systems such as neuronal cells or animal models. With this research proposal we will make good use of the antibodies we have recently developed with the financial support of the Advocacy.. In particular, we will analyse the feasibility of using some of these new antibodies for diagnostic purposes, in an attempt to improve the current assay based on Western Blot analysis.
The role of junctophili-3 (JPH3) in neurons- comparison to chorein (VPS13A) Dobrila D. Rudnicki at Johns Hopkins University, Baltimore Maryland, USA.
Huntington disease-like 2 is a neurodegenerative disease clinically and pathologically very similar to Huntington's disease and to chorea-acanthocytosis. The spiky red blood cells make it one of the four NA diseases. HDL2 is caused by a mutation in the gene junctophilin-3 (JPH3). The function of JPH3, the protein product of the gene,has not yet been characterized.
Here we propose to identify novel mechanisms and associated proteins by which loss of JPH3 protein expression, observed in HDL2 patients, may be involved in HDL2 pathogenesis. We also propose to explore whether similar mechanisms may be triggered by the loss of functional vacuolar protein sorting-associated protein chorein (VPS13A), which is implicated in chorea-acanthocytosis (ChAc).
By improving our understanding of JPH3 function and, in parallel, exploring potential points of convergence between the pathogeneses of HDL2 and ChAc, we may both advance our understanding of the pathogenesis of NA diseases, as well as facilitate the identification of novel targets for therapy.
