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INAD Gene Found
August 2006

New gene found! 
by Patricia Wood
 
An international team of geneticists, led by Dr. Susan Hayflick of Oregon Health & Science University and Dr. Eamonn Maher of the University of Birmingham in Manchester UK, discovered a new gene that causes NBIA. The finding, which is the second NBIA gene to be discovered, is significant because it will accelerate research into the disease and help scientists in their quest for a cure. 

The first gene, PANK2, believed to cause about half of NBIA cases, was discovered in 2001 by the laboratory of Dr. Jane Gitschier at the University of California, San Francisco in collaboration with the lab of Dr. Hayflick.

Discovery of the new PLA2G6 gene is documented in a study published in the July print issue of Nature Genetics. Researchers describe PLA2G6's discovery using DNA from families with a diagnosis of infantile neuroaxonal dystrophy, or INAD, and NBIA. A clinical test for this gene will be available in the next few months to help families with diagnosis and prenatal testing. 

It has long been thought there was an association between INAD, also known as Seitelberger disease, and NBIA. This new gene discovery confirms that, although there is still much to be learned about how this gene causes disease. 

Two seed grants from NBIA Disorders Association through the National Organization for Rare Disorders were used to help in the search for this gene. One was to Dr. Natalie Canham of the University of Birmingham in England in September 2003 and one was to Dr. Hayflick in 2004. It became an international effort with many groups participating and is a great example of how NBIA families and the association's research grants can make a difference and indeed already have! 

We asked Allison Gregory, a genetic counselor at Oregon Health & Science University, about the discovery. 

Q: What is the new NBIA gene?
A: The gene is named PLA2G6. This gene has been known and studied by researchers for some time, but nobody knew that changes in this gene could cause a disease. Our studies led us to discover that when a change, or mutation, occurs in PLA2G6, it will cause neurodegeneration. People with mutations in this gene may have been diagnosed with NBIA or INAD. We use NBIA as an umbrella term here, to encompass all the disorders that fall into this spectrum. 

Q: What is INAD? 
A: INAD stands for infantile neuroaxonal dystrophy. This is a progressive neurodegenerative condition that we started studying because many patients with INAD have brain iron accumulation similar to that seen in NBIA. Like NBIA, patients with INAD develop abnormal axons (a part of nerve cells) which are called spheroid bodies. Some of the people we studied with INAD do not have brain iron accumulation and we do not yet know why this is. 

INAD usually develops during very early childhood, causing loss of early milestones. Affected children eventually lose their ability to move or speak. Common features of INAD include optic atrophy and incomplete development of a brain structure called the cerebellum. Like PKAN and other forms of NBIA, INAD is inherited in a recessive fashion. This means both parents are carriers and an affected individual has no working copy of the gene. 

Q: Is INAD a form of NBIA?
A: We think so, but the answer is open to debate. Since many INAD patients have high brain iron and all have neurodegeneration, it does fit into the NBIA family of disorders. Also, we now know that the same gene can cause either NBIA or INAD depending on the type of mutation that occurs. We also believe that for many disorders there are other important genes, called modifiers, that also play a role and probably cause much of the variability that we see. As researchers and care providers, we find it helpful to think about all of these disorders together. 

Q: Why is the gene named PLA2G6? 
A: PLA2G6 is one of 18 lipid-metabolizing genes in a protein family known as phospholipase A2 (PLA2). The name designates that this gene is from group six (G6). 

Q: How does this gene cause the disease?
A: PLA2G6 is thought to encode an enzyme that breaks down lipids involved in the reconstruction of a cell's membrane following damage by light and other toxins. When the gene is mutated, lipid metabolism is altered and iron builds up, triggering disease. We do not yet know the specific details of how metabolism is altered or what causes iron to build up in this case. 

Q: How was the gene discovered?
A: We were able to find that mutations in PLA2G6 cause NBIA and INAD with the help of many affected families and many physicians in the U.S. and abroad who contacted us about their patients. Since most families with INAD are small and have only one affected child, it was very important for us to find several families and add all of their information together. This pointed us to a region where about 100 genes sit on chromosome 22. At the same time, scientists in England linked the INAD region of chromosome 22 with NBIA in a large family. 

Once our labs identified this region, OHSU worked on one half while our collaborators, Drs. Eamonn Maher and Neil Morgan at the University of Birmingham in England took the other half. This was very detailed work that involved searching through each gene systematically to find changes in the code that could cause the disease. It took many months of searching before the lab in England finally found the first changes in PLA2G6. We were quickly able to verify gene mutations in many of the INAD families that we had collected in our lab. 

Q: Is there a blood test for this gene? Is prenatal diagnosis possible?
A: Dr. Hayflick and her team are partnering with the OHSU DNA Diagnostic Laboratory to develop the test. Since Dr. Hayflick's lab is a research lab and has not been certified to do clinical testing, we cannot provide the testing on our own. Dr. Hayflick has close ties with the DNA Diagnostic Laboratory and will have continued involvement with providing the test for INAD and NBIA. We think the test will be ready in a few months. 

Once it is available, the test should take about three weeks to complete and will require a blood sample. For families in which the mutations can be identified in the affected child, prenatal diagnosis will be an option for any future pregnancies.

Q: Who should be tested? 
A: Families with children diagnosed with INAD or suspected of having INAD should talk to their doctors about the test. Since INAD is very difficult to diagnose, the genetic test could help confirm the diagnosis for many individuals. 

Our recent studies have taught us that people who were diagnosed with NBIA (not INAD) can also have mutations in PLA2G6. For this reason, people with NBIA who have tested negative for the PANK2 gene should ask their doctors about testing. Based on what we know now, it is likely that some people from this group will have changes in this gene. 

Q: Why is the discovery of this gene important for the entire NBIA community?
A: The discovery of the new gene provides an important piece in the puzzle of NBIA. Research can now focus on the workings of the cell that are disrupted when PANK2 and PLA2G6 are defective. PANK2 is important for energy metabolism, nerve signaling, cell membrane repair and other functions. PLA2G6 is involved in inflammation, programmed cell death, and membrane repair. The intersection of these two groupings is cell membrane health, which we think may be a problem common to all forms of NBIA. 

The new gene discovery also gives scientists a new target for developing NBIA therapies. Up till now, ideas for therapies have been focused on pantothenate, coenzyme A and iron. PLA2G6 functions differently from PANK2 in membrane repair. As we better understand its precise role in this process, new ideas for therapies will come. 

We don't have a cure yet for any of the NBIA disorders, but now is a good time to reflect on how far we have come in the past 5 years. Two major NBIA genes have been identified. An increasing number of scientists from around the world are working to advance understanding of the NBIA disorders. New symptomatic treatments have become available (e.g. deep brain stimulation). And the NBIA Disorders Association is gaining in strength (new research programs) and numbers (new members and affiliates). Our model of families working in close partnership with the research community is at the core of these successes.
 
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