At last! HSS gene found

Research 2001

  
An article in the August issue of Nature Genetics tells the facts in cool, scientific language: “A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz Syndrome.” What it means is that, after many years of searching, scientists have discovered the gene that causes HSS and have given it a name.

They have unraveled a major mystery behind HSS. Scientists have long focused on a buildup of iron in the brain as an essential feature of HSS, but the discovery points to something unexpected: A deficiency of an enzyme that puts phosphate on vitamin B₅ is even more significant. That deficiency is found in classical and atypical HSS.

The discovery of the gene is a giant leap forward in the quest for a cure to this devastating disease. The function of the gene, which is significant in developing treatments for HSS, is outlined in the article by the scientists who discovered PANK2: PhDs Bing Zhou, Shawn K. Westaway, Barbara Levinson, Monique A. Johnson, Jane Gitschier and Susan Hayflick, MD.

Hayflick was asked to give a score from 1 to 10 (with 10 being a cure for HSS) on the research status of the disease. She said that before finding the gene, scientists were at a 1— having very little information. Now, they have soared to about a 7, she said.

“Part of the reason our knowledge has expanded so rapidly is that research work done on a sister gene (PANK1) gave us important information,” Hayflick explained. “This gene was discovered approximately one year ago by a different group of researchers. When PANK2 was discovered it was obvious that it was very similar to PANK1 and the connection of both genes to pantothenate kinase was verified by researchers. Much information was already known about the protein pantothenate kinase which was discovered over twenty years ago. This furthered our knowledge about the gene and its functions.”

Even more important, many new researchers will now be interested in studying HSS because of its relationship to other diseases. The biochemical pathway of HSS is believed to have similarities to Parkinson’s and Alzheimer’s diseases. Also, researchers focusing on vitamin B₅ and cysteine will also want to learn more about PANK2.

Giovanna Spinella, program director/neurogenetics from the National Institute of Neurological Disorders & Stroke at the National Institutes of Health says a roll-up your sleeves session for researchers is being planned to set goals for the work ahead. Grants from NIH also are possible to further the research.

The discovery also has produced a new name for Hallervorden-Spatz Syndrome that describes it scientifically, based on the underlying biochemistry of the gene. HSS will now be known as pantothenate kinase associated neurodegeneration, or simply PKAN. It’s pronounced pee-can. By the end of this year, HSSA will announce our new name, too.
 

Since mapping the gene, Dr. Hayflick has joined forces with a group of scientists at the University of California at San Francisco. This team, led by Dr. Jane Gitschier, has identified several genes for human diseases. Dr. Gitschier and Dr. Hayflick believe their collaboration will speed up research to isolate the HSS gene. They believe they are close, but much work remains to be done.

Drs. Hayflick and Gitschier have recently received a research grant from the National Eye Institute to study Hallervorden-Spatz Syndrome. The grant is for five years and will be used to continue their work on HSS. Specifically, the research aims to identify the gene that causes HSS and determine the function of this gene in health and disease. This is an important first step towards understanding the process of brain nerve cell death and iron accumulation and will lay the groundwork to begin to develop rational therapies for this disease. In addition, once the gene is discovered and characterized, more scientists will focus their research efforts on this rare disease. The National Eye Institute, one of the National Institutes of Health, has supported Dr. Hayflick's research on HSS since 1995.

In addition to Drs. Hayflick and Gitschier, there is another research group based in Boston, Massachusetts, and includes researchers from Harvard Medical School and Dr. Donald Harter, former Chief of Neurology at Northwestern School of Medicine and currently Scientific Officer of the Howard Hughes Medical Institute. For several years, this group has been using human molecular genetic approaches to try and determine the molecular cause of HSS, according to team member Dr. Christine Seidman, a professor of medicine and genetics at Brigham and Women’s Hospital and Harvard Medical School.

“Through the cooperation and collaboration of families with affected individuals and the physicians who care for them, we have been able to refine the chromosome location of the disease gene,” Seidman said. “We are currently using several strategies to identify the causal gene and mutations. Our hope is that this information will improve diagnosis and allow insights into the pathophysiology which ultimately may provide insights into treatment.”

The group is continuing to recruit families into its study. Dr. Christine Seidman can be contacted at (617) 432-7871 or by e-mailing
cseidman@rascal.med.harvard.edu.

As many of you already know, gene discovery is moving rapidly. The Human Genome Project is an international 15-year effort launched in October, 1990, to discover all the 60,000 to 80,000 human genes. Once identified, further biological study can be done on the genes. The U.S. portion of the project is a collaboration between the Department of Energy’s Human Genome Program and the National Institutes of Health National Human Genome Research Institute. So far, the project has met or exceeded most of its goals ahead of time and under budget, said Francis S. Collins, director of the NIH research institute. Scientists expect this research to help them figure out how diseases work so they can cure them in advance. That would entail finding out what genetic disease a person is at risk for and replacing the bad gene with a normal, healthy one. This dream has already come true for some genetic diseases.
 

We have grand news to share with you. The gene for HSS has been identified. There have been times during the 10 years of this project when I wondered if this day would ever come, but the optimist in me knew we would succeed. The work was a collaboration between two very committed research groups and more than 135 families affected by HSS, including many of you, who contributed invaluable samples to this work.

Drs. Jane Gitschier, Bing Zhou, Barbara Levinson, Monique Johnson, and Shawn Westaway worked with me to accomplish this. The identification of the HSS gene is a major milestone in research of this disease, and it paves the way for us to unravel the mysteries of this disease. In addition, we anticipate that many more scientists will now join our efforts to understand HSS, and research progress will accelerate.

Through the HSSA, which serves a key role in communicating information about HSS and related disorders, we will keep you informed about our research progress.

Susan J. Hayflick, MD

Oregon Health & Science University

Q: Why is the discovery of the HSS gene such a big deal?

A: Before any disease can be treated effectively, scientists need to know what causes it. By locating the HSS gene, we now have, for the first time, critical knowledge about the function of the HSS gene and how the disease attacks the body. The discovery ultimately will make it possible to begin targeting medications and other therapies to patients who have the gene. But more research must be done first.

For example, we don’t know if vitamin B₅ or other supplements would be helpful or harmful to HSS patients. We must first unravel the biochemistry of HSS and see whether we can control changes in the brain with different medicines. We are beginning these studies very soon.

Q: What is the HSS gene?

A: We are naming the gene that causes HSS PANK2. This gene is found in every cell in the body, but in the case of patients with HSS, the PANK2 gene isn’t working right and is sending the wrong message to the cell.

We think the normal job of PANK2 is to use vitamin B₅ to make essential chemicals that the cell needs to generate energy and to fix the cell membrane. We think that PANK2 may have other jobs as well, and we are now trying to understand those functions.

Q: Why is the HSS gene called PANK2? That’s a strange name.

A: PANK stands for pantothenate kinase, the technical name for the enzyme that is encoded by the gene. There’s already a PANK1 gene, which is very similar to PANK2. “Pantothenate” is the chemical name for vitamin B₅. “Kinase” means that the enzyme’s job is to attach the chemical called phosphate to a target, in this case pantothenate. So, pantothenate kinase adds phosphate to vitamin B₅. Patients with HSS, however, don’t get the phosphate, causing a host of problems that we have identified as HSS symptoms.

Q: How does PANK2 cause HSS?

A: In patients with HSS the PANK2 gene is mutated, which means it has serious errors in the instruction code that makes it non-functional. Mutations are misspellings in the code of a gene. Since there are several PANK genes in humans (PANK 1, 2, 3, 4), we suspect that PANK2 might be especially important in the parts of the body affected in HSS, including the brain and retina.

When PANK2 can’t do its job, the cells die. We also think that another chemical called cysteine accumulates in brain cells and binds to iron to make the toxic effects of iron even worse. The cysteine comes from PANK2 not being able to do its usual job in the cell, a process that normally consumes cysteine. In HSS we think that the cysteine goes unused and then starts to build up and cause trouble.

We were surprised to find that both classical and atypical cases of HSS were found to have misspellings in the PANK2 gene. It appears that the type of misspelling seems to be the key to disease symptoms and their severity. Members of the same family will have the same misspellings. Though there may be other genes found that cause HSS, we feel the vast majority of individuals will have misspellings in PANK2.

Q: How did you discover this gene?

A: With the help of many families affected by HSS, we were able to map the gene. In other words, we took DNA from cooperating families, and that genetic material told us the HSS gene was in the neighborhood of chromosome No. 20.

Once we identified that region, we analyzed the codes of other nearby genes. We did this by looking at the spelling of the genes and comparing that to the spelling from people who don’t have HSS. We think there are about 20 to 25 genes in the HSS region. And each one had to be studied to see if there were any differences in the code. That took a long time.

But that careful work was finally rewarded. Researchers Bing Zhou and Barbara Levinson working in Jane Gitschier’s lab found the first PANK2 mutations. Shawn K. Westaway, a researcher in my lab, promptly found many more. When we compared the sequence of the code in PANK2 between affected and unaffected people, we were sure that we had the right gene. No unaffected people had a misspelling in both copies of their PANK2 gene.

Q: Is there a blood test now for HSS?

A: Yes. We are working with a clinical testing lab at the University of Chicago to do this. Medical testing can only be done in laboratories that are set up for this kind of work, and we knew that it would be very important to many families to have this test. The Chicago lab is specifically set up to offer genetic testing for rare orphan disorders, like HSS.

It is important to know that a normal gene test does NOT necessarily mean that a person does not have HSS. Although we think nearly all cases of HSS are caused by mutations in PANK2, other genes may also cause HSS. Since HSS is a group of genetic disorders, some families may have changes in genes other than PANK2. Therefore, in some families, the blood test for PANK2 will be normal even though they have HSS. We still have much to learn about HSS and its genetics.

Q: What does finding the HSS gene mean for research on HSS?

A: Now that we have identified the HSS gene, there are many directions for future research. There is a fruitfly that we think has HSS, and this fly will be important in our studies of the gene’s effects. We will also create a mouse with HSS by introducing a mutation into the mouse PANK2 gene. The mouse model is well along in its development and will be valuable in testing new therapies. We hope to have it completed in about a year.

Best of all, we expect many new scientists to be attracted to HSS research. Researchers studying vitamin metabolism, kinase function, cysteine accumulation, brain iron, retina disease and other related areas will be interested in this disease. In addition, those studying Parkinson’s and Alzheimer’s will want to study PANK2 since pantothenate metabolism may represent a common pathway in neural degeneration. We see the HSS gene discovery as a launching pad for scientists who now will take the research into many new directions, including work on treatments.

Q: What’s this about a new name for HSS?

A: Some of us have known for years that Hallervorden and Spatz, the two German doctors who first described the disorder, did unconscionable things during World War II. We waited to rename the disease until we had a sensible alternative. We now think that the gene discovery gives us a good basis for a new name, and we have renamed HSS. The disorder is now called pantothenate kinase associated neurodegeneration, or PKAN. It’s pronounced pee-can. We chose this name because it is a good description of just what is causing the disease.

A new name for HSS and HSSA

By Patricia V. Wood

I was horrified when I recently read of Julius Hallervorden’s activities in Germany during World War II. I had heard he had done unethical things, but the extent of his wrongdoing, including his role in the deaths of mentally and physically disabled patients, didn’t sink in until I read these articles.

I am sorry I used the name of Hallervorden and his boss and mentor, Hugo Spatz, for the organization I started. And now that Dr. Susan Hayflick and Dr. Jane Gitschier have identified the gene and renamed Hallervorden-Spatz Syndrome, I believe our organization should follow suit. Here’s why I feel so strongly:

Hallervorden was heavily involved in a selective “euthanasia” program that began in 1939 under the auspices of the Committee for the Scientific Treatment of Severe Genetically Determined Illness. That committee was established under the direction of Hitler’s Chancellery.

An article by Dr. Michael Shevell in the November 1992 issue of Neurology, a scientific journal, details Hallervorden’s role and its mandate: to exterminate retarded and malformed children.

Physicians registered these children and sent them to one of 28 institutions that had on-site extermination facilities. An estimated 5,000 children were killed, according to Shevell’s article. Some died after being deprived of food or heat. Others were gassed with cyanide or injected with morphine. Parents were told their children had died unexpectedly of an ailment, such as an appendicitis or pneumonia, the article says.

Another 70,273 adult mental patients were also killed in this extermination program using carbon monoxide in shower facilities. Shevell notes that while physicians were empowered to carry out “mercy killings” of adults and children, they were never required to do so, nor were they penalized for refusing. That, he said, made Hallervorden’s actions all the more heinous.

A post-war debriefing in the summer of 1945 by the American neuropsychiatrist, Leo Alexander, was part of a top-secret report in which Hallervorden spoke of his role in the program. Shevell’s article attributes the following quotes to Hallervorden:

But Hallervorden did more than passively receive autopsy material. He trained a physician responsible for selecting and killing patients on how to remove their brains. He also sent one of his lab technicians to assist at the extermination centers.

Hallervorden got plenty of research material. Shevell cites a letter Hallervorden wrote on March 8, 1944, to the program chief that said, “I have received 697 brains in all, including those which I took out myself in Brandenburg.”

On one day, Hallervorden arrived at Brandenburg and examined 33 children before they were executed. He then requested their brains for a research project called, “Inherited Feeble-mindedness,” according to Shevell. On a least one occasion, Shevell writes, Hallervorden also removed brains from selected victims immediately after they were killed.”

Spatz was director of the institute where Hallervorden worked, but his role is less clear. Perhaps, “he did not choose to inquire too closely into the details of a specific department’s work,” writes Peter S. Harper in a 1996 article in the British medical journal, the Lancet.

Shevell writes in a 1993 letter to the editor of the Lancet that when Alexander debriefed Spatz after the war, “Spatz lied by flatly denying that any member of his institute participated in the euthanasia program by receiving specimens from the killing centers.”

Harper’s 1996 article says the wrongdoing of Nazi-era scientists and clinicians involved in the deaths of the sick, handicapped and racial minorities is “of such enormity as to make it indefensible to use the names of those involved for disorders, even though their original descriptions may have involved no wrongdoing.”

Drs. Ruben I. Kuzniecky and Bradley K. Evans also argue in a 1993 letter to editor of Neurology that although Hallervorden and Spatz first described HSS in 1922, 17 years before the killing program began, the disease should not bear their names. A patient with “Hallervorden-Spatz disease” would have been a likely victim of the Nazi killing, Kuzniecky and Evans wrote. Indeed, one of Hallervorden’s assistants reported in 1940 that three patients at an extermination facility might have had “Hallervorden-Spatz disease.”

By the end of this year, HSSA will announce its new name. We expect it will include the new name for the disease or its acronym. Hayflick and Gitschier have christened it pantothenate kinase associated neurodegeneration (PKAN).

If you would like to read the articles mentioned in their entirety, you can find them at a medical library or online through Lonesome Doc.

References:

Shevell M, Racial hygiene, active euthanasia and Julius Hallervorden. Neurology 42; 2214-2219, 1992

Harper PS Naming of syndromes and unethical activities: the case of Hallervorden and Spatz. Lancet, 1996 Nov 2; 348(9036): 1224-1225.

Jacoby R, Oppenheimer C. Naming of syndromes. (Letter) Lancet, 1996 Dec 14; 348(9042): 1662.

Shevell M. Naming of syndromes (Letter) Lancet 1996 Dec 14: 348(9042): 1662.

Morrison P. Naming of syndromes (Letter) Lancet 1996 Dec 14; 348 (9042): 1662.

Gordon J, Julius Hallervorden (Letter) Neurology 43:1452, 1993

Kuzniecky R, Evans B. Julius Hallervorden (Letter) Neurology 43:1452, 1993

Updated - December 2001

Efforts to come up with a new name for HSSA are still underway but won’t bear fruit until next year.

In our last newsletter, we said that HSS families, physicians and researchers no longer want the disease to be named for Hallervorden and Spatz, two German doctors who participated in medical atrocities during WWII. When the PANK2 gene was identified earlier this year, researchers thought the vast majority of those diagnosed with HSS would have that gene. They proposed that the disorder be renamed pantothenate kinase associated neurodegeneration, or PKAN. We considered renaming HSSA the PKAN Alliance.

But nothing with this disease is easy. Researchers have since learned that many people who have HSS don’t have a PANK2 gene mutation. Consequently, the HSSA name will be around for a while longer as we search for a new name, an umbrella description, that will encompass all the various forms of HSS. Also a disease name for those without PKAN is now needed.

Parkinson’s is an example of a disorder that is a general umbrella term for many different diseases. Patients with Parkinson’s might have different gene mutations. As researchers discovered genes and identified causes of symptoms, patients were given a more specific diagnosis such as multiple systems atrophy.

We hope you will understand our decision to continue with HSSA at present. We will keep you informed and announce our new name in the coming year.

Within the next few months, the University of Chicago Genetic Services Laboratories will do genetic testing for HSS in patients and family members. The testing will identify the specific mutation of the defective gene in individuals who have HSS and will indicate whether family members are carriers.

Those being tested will have their blood drawn under orders from their family doctor, or a local geneticist, and the sample will then be shipped to Chicago for analysis.

Doctors strongly recommend that anyone being tested receive genetic counseling. Informed consent forms also must be signed, stating that the person understands the ramifications of being tested. The lab reports results to the ordering physician who also is responsible for pre-and post-test counseling of patients and family members.

The University of Chicago laboratory is a non-profit organization. They specialize in diagnosing and testing patients with rare orphan genetic diseases, where mutations in patients/families tend to be unique and differ from one family to the next, making genetic testing more of a challenge. Most clinical laboratories concentrate on genetic diseases that are more common within a certain population and where only one or few mutations are present, making testing simpler and more cost effective. Other rare diseases tested at the Chicago laboratory include lissencephaly, myotubular myopathy, Rett syndrome, Prader-Willi and Angelman syndromes.

HSS testing fees vary depending on the circumstances. For example, if the specific mutation analysis has previously been performed in a research setting, fees would be about $530 for the first family member and $390 for all others. If full gene sequencing is required, the cost would increase to approximately $1,000.

Some insurance companies may pay for the testing. The lab requires pre-authorization from the insurer. Otherwise, payment must be made in full before testing.

For more information, call the lab toll-free at (888) 824-3637 or at (773) 834-0555, in Chicago. The Web site also has information at www.genes.uchicago.edu. The e-mail address is ucgslabs@genetics.uchicago.edu.

The University of Chicago Genetic Services is now accepting clients for genetic testing for the PANK2 gene mutation. Contact genetic counselor, Patti Mills for details. She can be reached, toll free (U.S. only), at 888-824-3637 or at 773-834-0555 in Chicago. The e-mail address is ucgslabs@genetics.uchicago.edu. Information also is available at the Web site at www.genes.uchicago.edu.

The lab is a non-profit organization that specializes in diagnosing and testing patients with rare orphan genetic diseases. As researchers turn their attention to finding a therapy for HSS, the lab will help those who are interested in being tested for the PANK2 gene mutation.

Other yet-to-be-found genes likely involved in HSS
 

In a study from the Hayflick-Gitschier groups, 89 HSS patients out of 192 have been identified as carrying mutations in the PANK2 gene, pantothenate kinase. Evidence suggests that those with the PANK2 mutation have the “eye of the tiger,” a characteristic others with HSS don’t share. The sign shows up on an MRI as iron buildup in the globus pallidus section of the basal ganglia. It appears to be a bright white area with surrounding dark black.

Patients who don’t have a PANK2 gene mutation also have iron accumulation in the basal ganglia and share some of the same symptoms as PANK2 patients. Those symptoms can range in intensity from mild to severe. “They almost certainly have more than one disease, perhaps as many as three or four different diseases,” Hayflick said of those without the PANK2 mutation.

While researchers are not hunting for more HSS genes right now, they believe information about PANK2 will be useful to all HSS patients. Those with the PANK2 gene have difficulty metabolizing vitamin B₅, but even some HSS patients who don’t have the PANK2 gene mutation have responded favorably to B₅ supplements. Hayflick and Dr. Jane Gitschier are continuing their collaboration to learn more about the PANK2 gene. Their research is focused on five areas:

Bing Zhou admitted there were times when he wondered whether he and his colleagues would ever find the elusive gene that causes PKAN.

After four years of frustrated, trial-and-error searching, he finally succeeded this past spring while working as a researcher in the laboratory of Dr. Jane Gitschier at the University of California San Francisco. Subsequent studies afterward confirmed his findings.

“It was very frustrating,” Zhou said in an interview. “Once, after just two years, we thought we had identified the gene, but that turned out to be wrong. After three years, my colleagues were teasing me that I’d still be looking for this gene when my hair had turned gray.”

Zhou and other members of Gitschier’s and Hayflick’s teams concentrated their search on a specific area of chromosome 20 where they suspected the gene might be located.

“We were focusing our efforts on a small area of the gene and hoping it was the correct area, which it turned out to be,” he said. “I was very excited for one moment, then became calm, but happy. I told the others and they were very excited.”

Zhou discussed the discovery of the PANK2 gene in October at the American Society of Human Genetics conference held in San Diego. He was one of three finalists for a student award from the society in the post doctoral category for his work with the PANK2 gene, which is among the genes which cause HSS. As a “post doc,” Zhou has been transitioning from his studies to his first job, which he hopes will be doing independent research as a faculty member at a college.

Initially, he was interested in investigating the roll of copper in metabolism but turned to HSS after being introduced to the disease by a colleague. Now he believes a significant part of his future work will be with iron. Finding the PANK2 gene is a significant step forward.

Zhou is studying the PANK2 form of pantothenate kinase, the technical name of the enzyme that is encoded by the HSS gene. Pantothenate is the chemical 

name for vitamin B₅. Kinase means that the enzyme’s job is to attach the chemical called phosphate to a target, in this case pantothenate. So pantothenate kinase adds phosphate to vitamin B₅. Patients with PKAN, however, don’t get the phosphate, causing a host of problems that we know as HSS symptoms.

Zhou has also started working with other organisms to understand what causes iron to accumulate. A question to be answered is, why does iron accumulate only in cells in the brain? He is also looking for clues that could lead to a treatment for PKAN.

Zhou says much work remains to be done. Questions remain about the biology of the gene, but six months after its discovery, researchers are learning more all the time. Zhou is confident that one day the mystery of the PANK2 gene will be completely unraveled.