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.
Genetic testing of ChAc patients: the trouble with DNA analysis By Ruth Walker and Antonio Velayos
Ruth Walker
We have become aware of the fact that patients, or their relatives, clinically diagnosed with ChAc may be using commercial services to have a molecular confirmation of the diagnosis. During the last NA/NBIA meeting in Ede (The Netherlands), we received an email from a man whose daughter had just been diagnosed with possible ChAc. For particular circumstances, several members of the family had had their DNA analysed by 23andme, and he was trying to find out if the genetic information they got was enough to confirm the diagnosis of ChAc given to her daughter.
In this particular case, the genetic information relative to the VPS13A gene was not an exhaustive analysis of the DNA sequence, but of the kind known as “genotyping”. The human genome contains thousands of naturally occurring variations that are not pathogenic, that is, the sequence of the DNA in particular positions may be different among individuals. Genotyping is the analysis of the sequence that a particular person has in those positions. This information can be very useful but does not provide per se a molecular confirmation of ChAc.
What family members can do on receiving a probable ChAc diagnosis
Our recommendation to any person receiving a diagnosis of (probably) having ChAc, to their relatives and even their physicians if they are not experts in the field, is to seek the advice of a neurologist with previous experience with patients suffering from this condition. The first step should always be checking from the clinical information of the patient and the presenting symptoms whether or not the diagnosis of ChAc is likely or not. If the answer is yes, the next step should be having a simple blood test, known as the “chorein test”, which is currently offered free of charge in Munich (Germany) (https://www.euro-hd.net/edit/na/network/docs/na-blood-sampling-instructions.pdf), and is supported by the Advocacy for Neuroacanthocytosis Patients. This analysis consists in the detection of chorein in red blood cells. The results of such a test usually fall into three or four categories:
a. normal levels;
b. slightly reduced levels;
c. clearly reduced levels;
d. non-detectable levels of chorein.
The last two options (c, d) can be considered a positive diagnosis of suffering ChAc. The first two options (a, b) do not support a positive diagnosis but cannot be considered a definitive proof of a negative diagnosis either. Some mutations could lead to the presence of non-functional but detectable chorein. Genetic testing would only be required for confirmation of diagnosis when normal or only slightly reduced levels of chorein are detected.
Of course, even in the case of a “confirmed diagnosis”, there might be situations where a patient or his/her relatives would be interested in knowing the specific causative mutation(s). At this point it is important to state that ChAc is a recessive disorder, that is, affected people carry two mutated copies of the gene (one received from the father and one from the mother). Therefore, the progeny of an affected person would be carriers (they will have one copy of the mutated gene) but will not be affected. The only option to be affected would be that they receive another mutated copy from the other parent, a situation extremely unlikely unless a consanguineous relationship exists between the parents. Professional genetic counselling should be sought in such cases.
The wider context of genetic testing
Advances in technology for the analysis of the human genetic information have been relentless in the recent past, and will continue to do so at a probably faster pace in the near future. This has enabled not only the progress of laboratory-based research in human genetics and all related fields, but the possibility of non-scientists to be able to access information about their own genetic data. This is normally achieved by the use of commercial services that perform genetic analysis on a custom fashion. There has been much discussion, both in the medical and lay press, about the positive and negative implications of people having access to their genetic information in this way. For example, a man with Parkinson’s disease obtained his report, and found that it said that he was at lower risk than normal for PD.
In the context of Neuroacanthocytosis (NA), and in particular of Chorea-Acanthocytosis (ChAc), genetic analysis of affected or suspected patients has usually been performed on a research basis by groups with recognised expertise. To our knowledge, the use of commercial services for the genetic analysis of the gene VPS13A, altered in ChAc, has been very limited and we knew of only one of such service, in Germany, at a cost of around €3000 per sample. The costs of the analyses provided by different commercial genetic services varies and depends on the difficulty of the analysis as well as on the information given back to the customer.
For many conditions, the causative genetic changes are well known and/or the analysis of the affected gene from a technical point of view is not particularly demanding. Unfortunately, this does not apply to ChAc as the VPS13A gene has one of the most complex structures of the human genome, with 72 exons (individual components of the final molecule that will encode the protein). Furthermore, there are not “hot spots” where mutations occur as the pathogenic changes (leading to disease) found so far are distributed all throughout the gene. Thus, when using a commercial service, it is important that the patient receives not only specific information about his/her genetic data but a proper interpretation of their significance.
