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 Analysis of Lyn pathway in target cells from chorea-acanthocytosis and development of new chorea-acanthocytosis mouse model Dr. Lucia de Franceschi in Verona University of Verona, Italy
Dr. Lucia de Franceschi and her group at the University of Verona in collaboration with EMINA I and II network is analyzing the Lyn pathway on target cells from chorea-acanthocytosis. We are working on new targets of Lyn in red cells from patients with chorea-acanthocytosis. We have set up in vitro cultures of erythroid precursors from peripheral CD34+ cells to study the impact of the absence or reduction of chorein on erythropoiesis. We will present some preliminary data at the Vienna meeting of EMINA network. Finally, in collaboration with the University of Torino, we have also started a program to generate a mouse model for chorea-acanthocytosis, which will be shared in the NA scientific community if we get it surviving for biomedical studies.
Functional Characterisation of chorein Dr. Antonio Velayos-Baeza Wellcome Trust Centre for Human Genetics, University of Oxford, UK
We have continued our work on ChAc which, as mentioned in our last report for NANews, is focussed on the functional characterisation of the protein VPS13A, also known as chorein, and in the analysis of the effects of particular mutations found in ChAc patients. The coding sequence of the VPS13A gene is expressed in mammalian cell lines commonly used in the laboratory and the localisation of chorein is compared with specific markers for different sub-cellular compartments. Some of the pathogenic changes found in ChAc patients are also checked in the same way, and compared with normal chorein. These studies aim to gain some insight into the role of different protein regions that may be relevant for aspects such as sub-cellular localisation or stability of the protein.
We are also involved in a number of collaboration projects with other researchers, including the characterisation of mutations from a number of ChAc patients or the generation of specific plasmids for the expression of human VPS13A coding sequence in a fly model developed by the group of Prof. Ody Sibon.
The role of XK protein in Erythrocyte ion Transport Function Alicia Rivera, MS, PhD, Boston Children’s Hospital / Harvard Medical School, Boston
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 to 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 nonsense 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.
Functional analyses of ion channels in Chorea-Acanthocytosis (ChAc) patient-derived induced pluripotent stem cells and differentiated neurons in vitro. Department of Neurology, Hannover Medical School, Germany F. Wegner, N. Stanslowsky, A. Storch, A. Hermann
The aim of this research project is to gain insight into the functional pathomechanisms of Chorea-Acanthocytosis (ChAc). Previously, 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 two healthy control iPSC lines have been differentiated into neurons to study their synaptic activity, ion channel and action potential properties. As particular striatal interneurons are the main target of neurodegeneration in ChAc, we have established an efficient iPSC differentiation protocol producing a large population of medium spiny GABAergic neurons for functional analyses. Our recordings suggest a pathological excitability of ChAc neurons which may be linked to clinical symptoms like hyperkinesia and epileptic seizures and could represent a relevant therapeutic target to treat ChAc. Future studies will have to identify the detailed molecular pathomechanisms and a potential drug reversing this pathological hyperexcitability of ChAc neurons with the goal to render an effective neuroprotective treatment.
Vps13a regulation of phosphatidylinositolphosphate pools in mammalian cell Aaron Neiman, Stony Brook University, New York
Aaron Neiman’s paper "SPO71 encodes a developmental stage-specific partner for VPS13 in Saccharomyces cerevisiae" has been accepted for publication in Eukaryotic Cell and we have just submitted another manuscript to J Cell Science. The study is on the interactions of Spo71 and Vps13. Spo71 is expressed only when yeast cells form spores. When it is expressed, the Spo71 protein binds to Vps13 and causes Vps13 to relocalize from the endosome to a different intracellular location, the prospore membrane. At this membrane, the two proteins collaborate to regulate lipid composition.
