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AFTD The Association for Frontotemporal Dementias 1616 Walnut Street, Suite 1100, Philadelphia, PA 19103 www.FTD-Picks.org New Genetic Defect Identified in Some Cases of Inherited FTD On July 16, 2006 in the scientific journal Nature two separate groups of researchers reported new gene mutations that appear to be responsible for hereditary FTD in approximately 5% of families with the disease. The gene involved is called PGRN, is located on chromosome 17, and codes for the protein progranulin. This finding, although important, is relevant for only a small number of FTD patients and their families with a clearly established, inherited form of FTD. For the vast majority of cases of FTD the importance of these new mutations is less clear. Nonetheless, the identification of this new genetic cause of FTD in even a small group of cases is another important piece in the FTD puzzle, and one that opens up new and important avenues of research. The majority of patients (40%-75%) have a form of FTD that is sporadic—meaning that the disease happened by chance in that individual, there is no family history of FTD, and there is not a single major genetic cause. In this group there appears to be little, if any, risk of recurrence in family members, and the current findings have no immediate impact. In other families, based on the number of FTD and FTD-like diagnoses in the family, doctors suspect that there is a genetic (inherited) component to the disease. Before these current results were published, researchers had identified one specific gene responsible for a significant proportion of hereditary FTD. This is the MAPT gene (also, by chance, located on chromosome 17), which codes for the protein tau. Tau’s normal role in the brain is to stabilize the neurons, which enables them to function normally. FTD patients with mutations in the MAPT gene produce abnormal versions of the tau protein. The result is neurons that are less stable than normal, and thus don’t function properly. But only about 10% of FTD patients have a mutation in the MAPT gene, so scientists have long suspected that there are other genes that can cause FTD. This is confirmed by these current publications, which show that about 5% of FTD patients have a mutation in the PGRN gene. The PGRN gene contains instructions that tell cells how to make the protein progranulin. Progranulin is a factor that stimulates cell growth and wound repair, although too much progranulin has previously been linked to some cancers. Although the precise role of progranulin in brain cells is unknown, FTD patients with PGRN mutations do not produce enough functional progranulin. How this relates to the premature degeneration of nerve cells in the frontotemporal region of the brain in FTD is unknown. Identification of mutations in the PGRN gene as one cause of FTD is of immediate importance only to families with a strong hereditary pattern of FTD related disorders, and who are known to lack a mutation in the MAPT gene. If a PGRN mutation is found in these families, almost certainly it would be the cause of the FTD for those individuals. At this point, as there is no definitive therapy for any form of FTD, and the identification of the mutation would be largely valuable for research purposes, although under special circumstances members of an involved family may consider individual genetic testing. This research is important because it demonstrates another mechanism that can cause nerve cell degeneration in FTD. Once the precise mechanism by which reduced progranulin causes disease has been identified, it may lead to promising new avenues for treatment. This is likely to take many years, however. Q&A 1. For families without a known family history of FTD, what is the importance of this finding? For families that do not exhibit a clear pattern of FTD being passed from generation to generation, the identification of the PGRN gene has no immediate impact on care or our understanding of the cause of FTD in your family. This applies to the majority of FTD patients. It is important to consider consulting a genetic counselor familiar with FTD and related disorders to help you understand whether your family has a strong history of FTD that warrants additional testing. FTD researchers nevertheless are very excited about this new information, as it is an important step forward in our basic understanding of what can cause neurodegeneration on the frontotemporal region of the brain (and thus cause FTD). This research indicates that a functional PGRN gene (one that contains the instructions for the neuron cell to make the growth factor progranulin) may be necessary for the neuron to survive and work properly. This is an important piece of information that suggests a new avenue for the development of effective therapies: Researchers will now investigate the role of progranulin in neuronal functioning and whether substances related to progranulin might serve as the basis for future drugs to treat FTD. 2. What will the doctor do differently if a PGRN mutation is identified? If a PGRN mutation is identified in an FTD patient, it means that the diagnosis of FTD is confirmed (for the vast majority of FTD patients, the diagnosis cannot be conclusively made until autopsy). It will also identify the specific cause of FTD in that patient: an error (mutation) in the PGRN gene means that their brain cells cannot produce enough functional progranulin, and without a sufficient amount of this substance, neurons in the frontotemporal region of their brain are dying. At this point there is no apparent impact on clinical care (just as there is none for those with a defect on the MAPT gene that codes for tau). Identification of a PGRN mutation would also have an impact on the patient’s relatives. Just as with MAPT, if a specific mutation is identified, some family members will be eligible for presymptomatic genetic testing. This means that a blood test, analyzed in a laboratory that is certified to carry out this type of genetic study, could tell them whether or not they inherited the same PGRN mutation, and thus whether or not they themselves eventually will develop FTD. The decision to have such testing requires careful consideration with a genetic counselor of all the possible implications of knowing whether or not an individual is a gene carrier. This is necessarily an involved process so that there is thorough understanding of the ramifications of having this knowledge. 3. Could a PGRN mutation cause FTD, even if there is no family history? It is possible. The age of disease onset in the PGRN cases varies considerably and can occur at an older age (>70 yrs). This raises the possibility that previous members of the family might have had the mutation, but died of other causes, before FTD would have developed. Other possibilities include that a PGRN mutation may occur as a new mistake in the patient, or that there may be a problem in the cell mechanism that produces progranulin even if the genetic instructions are correct. These possibilities are some of the next questions scientists will begin to address. 4. How do I know if a mutation in the PGRN gene is the cause of FTD in my family? The first step is to determine whether FTD is inherited in your family. We recommend that you read the new AFTD publication "The Genetics of FTD: Should You Worry?" to learn how to collect your family health history and to get a basic understanding of genetics and genetic testing. (The booklet is available online or hard copies can be ordered from the AFTD office for a nominal fee.) The next step is to work with your physician and/or a genetic counselor. They will compile all of the information and discuss whether or not genetic testing might be informative for your family. (To find a genetic counselor who specializes in FTD and/or other neurodegenerative diseases, contact your clinician or go to www.nsgc.org) 5. Do mutations in the PGRN gene produce a specific subtype of FTD? Is there any specific clinical symptom that would suggest that a PGRN mutation is responsible? There is a statistical tendency for individuals with a mutation of the PGRN gene to have progressive aphasia. This is a disorder of language known to occur in FTD. Conversely, tentative results from these early studies suggest patients with PGRN mutations are much less likely to have motor neuron disease (ALS) than are FTD patients without a mutation in this gene. These associations will have to be confirmed by multiple studies before we can be sure they are not chance occurrences in the patients studied thus far. 6. Have any differences been identified between FTD that is caused by mutations in the MAPT gene vs. mutations in the PGRN gene? Yes. The two genes code for two distinct proteins that each has their own function: MAPT codes for tau, which provides structure to support the neuron, and PGRN codes for progranulin, which may play a roll in cell growth and repair. Scientists have known for many years that different proteins may accumulate abnormally in the brain cells of FTD patients. One common cellular profile they see is due to abnormal amounts or versions of the protein tau. A few years ago scientists discovered that some of these cases were due to mutations in the gene that codes for tau, the MAPT gene. These new findings explain a second type of cellular pathology that scientists see in some FTD patients. A mutation in PGRN is associated with the accumulation of abnormal amounts of the protein ubiquitin in neurons. The connection between ubiquitin and progranulin is not yet fully understood. Ubiquitin is usually attached to other proteins—it is the cell’s way of marking damaged or misshaped proteins for disposal. Scientists are currently trying to determine which proteins are attached to ubiquitin in patients with this form of FTD, since it may help to reveal how mutations in PGRN cause the disease. 7. Is it just coincidence that both the MAPT and PGRN genes are located near each other on chromosome 17? Our current understanding is that this is just a coincidence. The two genes code for two distinct proteins with two different functions. They just happen to be located near each other (like two different books that just happen to be on the same shelf). The density of genes in this region of chromosome 17 is known to be one of the highest observed in the entire human DNA sequence. This increases the possibility that multiple genes linked to the same disease will be found close to another by chance alone. 8. What next? Even if the identification of the PGRN gene does not impact you or your family today, we should all take encouragement from the fact that scientists around the world are researching FTD, and making important strides in our understanding of this disease. It is always important to identify a genetic abnormality that is associated with a disease. This adds another piece to solving the FTD puzzle. Hopefully it can point the way towards a molecular basis for a treatment for this subtype of FTD, but we are likely many decades away from that. It is important to remember that these results only apply to a subgroup of familial patients and not to sporadic cases. -- Jordan Grafman, Ph.D. NINDH , National Institutes of Health and member of the AFTD Medical Advisory Council. The finding of mutations in PGRN is incredibly important for our research. At last we know what causes this genetic form of FTD and we can now start to determine the disease mechanism, which is the first step to therapy. Although only around 5% of FTD patients appear to have mutations in PGRN, a much larger proportion have the same neuropathological changes in their brains. As a result, by understanding how PGRN mutations cause FTD we are likely to have a much clearer idea of the disease mechanism in this larger group of cases. --Michael Hutton, PhD., Mayo Clinic, AFTD Medical Advisory Council The results of these two studies open the door to valuable new avenues of research that scientists will now pursue. The important work of Hutton, von Broeckhoven, and their colleagues will lead to new diagnostic tests for identifying the cause of FTD in some patients. It is important to keep in mind that these important new findings will have an immediate impact only for a small number of individuals with FTD. With additional research funding from NIH and other sources, scientists will be able to take advantage of these findings to develop new therapeutic strategies for treating a large number of individuals with FTD. --Murray Grossman, MD, PhD. Chair, AFTD Medical Advisory Council Click here to see copies of the actual studies: Mayo Clinic Study von_Broeckhoven Study Click here to see a copy of the July 17th announcement in Nature.com