NBIA FAQ >>>
An Interview with Dr. Susan Hayflick
 
September 2002

An Interview with Dr. Susan Hayflick and Jason Coryell

Q&A on Neurodegeneration with Brain Iron Accumulation and Current Research

Neurodegeneration with Brain Iron Accumulation, (formerly Hallervorden-Spatz Syndrome), as some of you know, is a confounding, bewildering disease. There is much we still don't know about it. In the following Q&A, Dr. Susan Hayflick, a geneticist and pediatrician at Oregon Health & Science University, tries to take some of the mystery out of it. She has been studying NBIA since 1992, and has been successful in finding the gene that causes the most common form of NBIA. Her opinions may vary somewhat from other researchers in this field. 

Q: What causes NBIA?
A: NBIA is a rare, genetic condition that causes movement disorders as well as iron build-up in the brain. We don't know why this happens, but research has shown that the iron settles primarily in the brain's control center for the body's movements - the basal ganglia. What makes NBIA all the more puzzling is we don't know yet if iron is causing the disease or if it is the brain's response to the disease, much like a scar in the skin's response to a cut. 

Actually, NBIA is probably more than just one condition.  It is more like a family of related conditions with similar symptoms.  The most common genetic form of NBIA was determined in 2001 when researchers at Oregon Health & Science University (OHSU) and the University of California at San Francisco (UCSF) discovered that at least 50% of NBIA patients have mutations in the gene PANK2.   Individuals who have mutations in the gene are said to have PKAN (pantothenate kinase associated neurodegeneration).  Patients who don’t have mutations in this gene still have a form of NBIA--we just don’t know which gene is causing the disease yet. 

In all cases of PKAN and most cases of NBIA, the condition is recessively inherited.  This means that the person with NBIA inherited a copy of the defective gene from each parent.  The parents have no health problems and are said to be carriers for the condition. 

Q: What are some of the symptoms of NBIA and when does it strike its victims?
A: I believe that not all NBIA is the same disease. The most common form of NBIA, also known as PKAN, has very distinctive features.  In the early childhood form of PKAN, patients develop uncontrolled muscle spasms (dystonia), and at least 2/3 have progressive peripheral vision loss (retinitis pigmentosa). The muscle disorder will often affect speech and possibly swallowing.  The combination of vision loss and dystonia usually causes the first noticeable symptom of frequent falling. 

There is also an adolescent or adult onset form of PKAN, and the presenting symptom is usually speech problems (repetitive, rapid, slurring). Other features may include problems of thinking (dementia) or sudden emotional changes.  The movement disorder is characteristic, but it usually develops later and is more slowly  progressive than the childhood form of the disorder.

Other forms of NBIA also have movement disorders, but may include other symptoms, such as seizures or mental retardation.

Q: How do doctors treat patients with HSS?
A: To be honest, treatment for HSS has been disappointing. Many drugs are available to help control the muscle spasms and contractions that occur in HSS patients, but no therapy has been found to treat the cause of HSS. 

Treatment plans differ from patient to patient.  The same treatment regimen is not equally effective for everyone because there are different genetic forms of the disorder and every person’s chemical reaction to medications is slightly different.  For this reason, families have to work closely with their neurologist to find a combination of medications and dosages to which the person is most responsive. 

Q: Why not give a drug to remove iron from the brain?
A: That is not as easy as it sounds. The few drugs that can do this do not seem to have much impact on people with NBIA. These drugs, called iron chelators, most often cause an iron deficiency in the body of patients before there is an appreciable lowering of brain iron.  However, new drugs are being developed that could prove more effective for lowering brain iron. We're just not there yet. 

Q: Explain how the inherited genes cause NBIA.
A: We know that PKAN and probably most other forms of NBIA are caused by a gene that is not properly coded.  This would be like reading a book chapter and coming across a typo that changes the meaning of the sentence. 

Genes are the blueprint instructions that are passed on in the egg and sperm to help a newly conceived embryo develop. Genes are packaged in structures called chromosomes. We inherit half our our chromosomes from our mother (in the egg) and half from our father (in the sperm), so half of our genes come from each parent. PKAN is an autosomal recessive genetic condition. This means that two copies of the misspelled gene, one from each parent, are necessary in order for the disease to occur. Other forms of NBIA are probably also caused by misspelling, but in different genes. 

Q: What are the chances of HSS occurring again in a family with one child already affected by it?
A: Each parent, if not affected themselves by HSS, has one misspelled copy and one correctly coded copy of the HSS gene and is, therefore, a carrier of the disease. There is a one in four chance (25%) that HSS will occur in each subsequent pregnancy. Males and females are equally likely to be affected. Because of the odds, many parents with one HSS child are fearful of having more. 

If a carrier parent has a pregnancy with a different partner, the chances are probably much lower.   If the new partner is in no way related to the affected child, the chance that he/she is a carrier is pretty low.  Likewise, a pregnancy with a sperm or egg donor reduces the likelihood of having another child with the same condition.  The chance that any person in the general population could be a carrier for a form of NBIA is somewhere between 1/275 to 1/500. 

If you are related to someone with NBIA and considering a pregnancy, you can discuss the risks and possible testing options with a genetic counselor in your area. 

Q: Tell us about your research.
A:  Our laboratory at Oregon Health & Science University works jointly with Dr. Jane Gitschier’s group, from the University of California, San Francisco. Now that PANK2 has been found, we want to understand why mutations inside it lead to symptoms like neurodegeneration and retinitis pigmentosa.  We want to compare the normal sequence with the “misspelled” version in patients.  We hope that the gene discovery will lead us to understanding the biochemical pathway better, and eventually this may help us find new treatment options.  As with most research, one answer generates many new questions.  Some that we are facing now include: How does the misspelling cause iron to deposit in the brain? What is the normal function of PANK2? Are other forms of NBIA caused by misspellings in related genes? 

Q: How far along is your research?
A: Finding the PANK2 gene was a major milestone, and now we know the exact mutations causing disease in several dozen families.  This helps us to correlate the type of mutation with the clinical symptoms.  We are also in the process of studying the effect of gene mutations in other living systems, such as yeast, fruit fly, and mouse.  We have started clinical studies to look for other biochemical differences in patients with PKAN.  We are continuing clinical studies that will lay the groundwork for being able to offer clinical trials in the future. 

Q: What can NBIA families do to help further your research?
A: Many families have contributed blood to assist with finding the gene.  Now that we have found the gene, we no longer do testing on a research basis (see University of Chicago for testing info). 

We have an international registry in which we collect clinical information, and in some cases, biological specimens, from families. Families interested in participating in our research can contact us at: (503) 494-4344 or coryellj@ohsu.edu.   We will collect contact and clinical information for the registry.  In some cases, we may just want medical records to understand the clinical history.  In other cases, we may request blood samples from family members for current or future research plans. Because this is a rare disorder, simply sharing your information can be a valuable gift for helping us to plan future directions in our clinical research.

  

 
1998-1999
Q&A on Hallervorden-Spatz Syndrome and Current Research

Hallervorden-Spatz Syndrome, as some of you know, is a confounding, bewildering disease. There is much we still don't know about it. In the following Q&A, Dr. Susan Hayflick, a geneticist and pediatrician at Oregon Health & Science University, tries to take some of the mystery out of it. She has been studying HSS since 1992, and has been successful in mapping the gene that causes the most common form of HSS. Her opinions may vary somewhat from other researchers in this field.

Q: What causes HSS?
A: HSS is a rare condition caused when a defective gene is inherited from both parents. We have not yet discovered how this gene causes the disease, but we do know it results in a high concentration of iron in the brain. We don't know why that happens, but research has shown that the iron settles primarily in the brain's control center for the body's movements - the basal ganglia. What makes HSS all the more puzzling is we don't know yet if iron is causing the disease or if it is the brain's response to the disease, much like a scar in the skin's response to a cut.

Q: What are some of the symptoms of HSS and when does it strike its victims?
A: I believe that not all HSS is the same disease. The most common form of HSS, which I call classical HSS, has very distinctive features: iron deposits in the brain, night blindness (retinitis pigmentosa) and uncontrolled muscle spasms (dystonia). Other features may include difficulty with speech (dysarthria), problems of thinking (dementia), seizures, uncontrolled writhing movements (chorea) and tremor. Classical HSS nearly always has its first signs in childhood. But HSS also has been known to strike adolescents and adults.

Q: How do doctors treat patients with HSS?
A: To be honest, treatment for HSS has been disappointing. Many drugs are available to help control the muscle spasms and contractions that occur in HSS patients, but no therapy has been found to treat the cause of HSS.

Q: Why not give a drug to remove iron from the brain?
A: That is not as easy as it sounds. The few drugs that can do this do not seem to have much impact on people with HSS. However, new drugs are being developed that could prove to be effective someday. We're just not there yet.

Q: Explain how the inherited genes cause HSS.
A: We know that classical HSS and probably most other forms of HSS are caused by a gene that is not properly coded. Genes are the blueprint instructions that are passed on in the egg and sperm to help a newly conceived embryo develop. Genes are packaged in structures called chromosomes. We inherit half our our chromosomes from our mother (in the egg) and half from our father (in the sperm), so half of our genes come from each parent. Classical HSS is an autosomal recessive genetic condition. This means that two copies of the misspelled gene, one from each parent, are necessary in order for the disease to occur. Other forms of HSS are probably also caused by misspelling, but I now believe that they are misspellings in different genes.

Q: What are the chances of HSS occurring again in a family with one child already affected by it?
A: Each parent, if not affected themselves by HSS, has one misspelled copy and one correctly coded copy of the HSS gene and is, therefore, a carrier of the disease. There is a one in four chance that HSS will occur in each subsequent pregnancy. Males and females are equally likely to be affected. Because of the odds, many parents with one HSS child are fearful of having more.

Q: Tell us about your research.
A: We are trying to identify the precise gene that is responsible for this condition. Once we find the classical HSS gene, we can begin to study it and start on the path toward what we hope will be a cure for the disease. We need to know how and when the gene is misspelled and how that causes the disease. And there are many more questions" How does the misspelling cause iron to deposit in the brain? What is the normal function of the HSS gene? Are other forms of HSS caused by misspellings in related genes?

Q: How far along is your research?
A: We have been successful in mapping the gene that causes classical HSS by using a genetic technique called linkage analysis. That gave us the general address for the gene but not an exact location. It's like knowing a house is in a certain city, but still not knowing the street address. We have localized the gene to a very small region on one of the chromosomes near the top of the short arm of the #20 chromosome. We say it is located at 20p13. We tested families with HSS from all around the world, and these tests all point to the same location. Now we must identify the exact gene.

Q: What can HSS families do to help further your research?
A: We are now offering genetic testing for some families with one or more affected members.  Testing in on a research basis and is done for no charge. Our research has greatly benefited by family participation. Over 70 families have contributed blood samples, which were critical in our progress to find this gene. We have an international registry of that 150 individuals, which will continue to be a valuable resource in future research. Families interested in testing or in participating in our research can contact me at: (503) 494-6866 or E-Mail me at: hayflick@ohsu.edu . Also, I am working with Dr. Jane Gitschier, from the University of California, San Francisco. She can be reached at (415) 476-8729. Dr. Gitschier and I urge families to contact us. We want to help.