The Genetics of FTD: Should you worry?

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EXECUTIVE SUMMARY

In 2007 there is still more that we DON'T understand about the genetics of FTD than we DO understand. Researchers and families are working together around the world and each year the picture comes into focus a bit more.

Our current understanding of the genetics of FTD is summarized in the following:

* For most families (40-75%) FTD is sporadic. This means the disorder is not being inherited, and the risk to family members is the same as that of any individual in the general population.
* For a small minority (about 10%) of families, FTD is being inherited, and each first-degree relative of the patient (siblings and offspring) has a 50% chance of having the same disease-causing gene mutation and thus developing the disorder.
* A large group of families (20-50%) lie in a mid-range, where family history reveals that there is a heritable component to the disorder, though it appears to not be as strong as that in the "inherited" group. Family members in this group are at elevated, but not yet clearly defined, risk for developing FTD. This inheritance pattern is termed familial.

To determine which of these situations best describes the FTD in your family, we suggest that after reading this information you seek professional advice from a specialist in neurogenetics.

Given that advances are continually being made, it is important to stay abreast of developments in this rapidly changing field. One of the best ways of doing this is to stay connected with AFTD.

This article contains the following sections:

* Introduction
* The Importance of Your Family Medical History
* Genes and Inheritance: Understanding the Basics
* The Genetics of FTD
* Genetic Counseling and Genetic Testing
* Discussing These Issues with Your Family
* References
* For More Information


INTRODUCTION

One of the most distressing aspects of a diagnosis of FTD is the fear that the disorder may be inherited, indicating that the patient's children or siblings might be at increased risk for the same condition. Although the genetics of FTD are not completely understood, research programs throughout the world are increasing our knowledge each year, and, thanks to the generous participation of patients and families, the general picture is beginning to come into focus.

Research continues to show that the proportion of FTD cases with a strong genetic component is small, although the extent to which genetics plays a role in the majority of cases is not as clearly understood (see graph above). This review provides a summary of our current understanding of the genetics of FTD, some basic information on genetics that will help you better understand this summary, and advice on important steps you can take to best clarify the inheritance risks in your own family.

When asking questions about your own family's situation, it is important to keep a few general principles in mind:

* Because FTD is actually several different diseases, there is no one answer to the question: "Is FTD genetic?"
* The answer to: "Is FTD being inherited in my family?" can best be found by working with a trained health professional (genetic counselor) and by gathering accurate information from family members.
* Accurate genetic risk can only be determined if there is an accurate diagnosis. Some FTDs cannot be accurately diagnosed until autopsy; this is an important issue to discuss with your clinician. Genetic counseling is essential to help identify and accurately interpret risk, provide education, and explore the benefits and limitations of genetic testing for you and your family.
* Whereas we once thought of disorders as either being genetic (inherited) or not, modern science is revealing that many, if not most, medical conditions fall in the middle, gray area: The genes one has inherited provide a general background risk (low, average, or high) for a condition, and specific factors in an individual's life: behaviors, environment, even chance -- determine whether the person actually develops that disorder. This appears to be the case with most FTDs.
* For many families, the answer will lie (frustratingly!) in this middle, gray area, where it appears that the risk to family members is higher than that of the general population, but no specific risk number can be quoted, and the precise cause of this elevated risk is not yet known. In such cases it is a good idea to stay in touch with your medical team (and AFTD), as new information on your family and research advances may enable them to re-evaluate and give your family a more specific risk in the future. There is no question that genetic testing will improve and prove to be a valuable diagnostic tool in the future for more families and individuals with FTD.

One of the difficulties of researching the genetics of FTD is that it is so rare. Scientists need cases and cases are hard to find. Research programs are critically important to this effort; it is only through the generous participation of patients and their families that we will advance our understanding of the role genetics plays in FTD.


THE IMPORTANCE OF YOUR FAMILY MEDICAL HISTORY

When a physician or healthcare provider is evaluating a patient for a diagnosis of FTD or similar neurodegenerative condition, information regarding the family history can help determine a diagnosis. Thus, a detailed family history is a valuable diagnostic tool. It is worth the time and effort to contact relatives and obtain the most accurate details of family structure and medical information. A complete family history that describes family structure and health history contains a lot of information. It is important to document the information in a meaningful way that is accessible and easy to read. (For more information on the importance of knowing your family's health history, and tools to help you gather and organize the information, see the U.S. Surgeon General's Family History Initiative at www.hhs.gov/familyhistory.)

Geneticists and genetic counselors create a pedigree, which is a graphic description of family structure and health history, to record information collected from patients and families. Determining the quantity and quality of information to collect can be difficult. Ideally, one should research at least three generations of relatives, which includes:

* First-degree relatives: children, siblings, and parents
* Second-degree relatives: half siblings, aunts, uncles, nieces, nephews, grandparents, grandchildren
* Third-degree relatives: cousins

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The type of medical information to obtain on relatives can include:

Vital Status (Living or deceased)
Age (Date of birth)
Age at death
Cause of death
Autopsy (if one was performed)
Pregnancy, miscarriages and stillbirths
Infertility
Individuals with previous genetics evaluation
Environmental exposures
- Radiation, alcohol or drug abuse, tobacco
Health history
- Birth defects
- Mental retardation
- Deafness, blindness
- Chronic childhood illness
- Cancer
- Neurological conditions (e.g. epilepsy, migraines, strokes, multiple sclerosis, Parkinson's disease, ALS (Lou Gehrig's disease))
Mental illness (e.g. bipolar disorder, schizophrenia, OCD)
Dementia (Alzheimer disease, senility)
Ages of diagnosis for all of the above
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When going back and obtaining medical information from previous generations, it is important to note that many of the medical terms we use today, such as FTD and Corticobasal Degeneration, were not used. Therefore, many individuals with neurodegenerative conditions would have been told that they had "dementia" or "senility". In such cases, it can be useful to try and gather more descriptive information. For example, it is useful to ask if the individual had problems speaking as a first symptom, or if he/she had a personality or behavior change. It is also important to try and determine an estimate for the age of onset.

Another way to determine diagnosis in deceased relatives is to inquire about autopsy. If an individual had an autopsy, the autopsy records (as well as other records, MRI reports and brain biopsies) can be requested and these records can be most informative. Confirmation of diagnoses with medical records from previous evaluations and laboratory studies is also crucial.

The family medical history, or pedigree, can be a powerful diagnostic tool to a clinician evaluating a patient. The pedigree can be utilized as a diagnostic tool in the following ways. To:

* establish pattern of inheritance;
* identify individuals in the family at-risk for the condition;
* determine strategies for genetic testing; and
* help screen for medical risks (such as cancer and heart disease).

Family history information needs to be respected and treated appropriately by healthcare providers and individual family members. Contacting relatives and asking about personal information is not an easy task. Navigating through the complex interpersonal relationships and personalities in a family can be emotionally difficult and stressful. This is a give-and-take process: When calling a relative, it is important to state your intentions or reason for collecting the information. Offer to re-contact family members with information that you learn about your loved one's diagnosis and how it may affect them. Respect an individual's right for privacy. If you go through the effort of obtaining a family history, be sure to document the information clearly and secure it in a location that is accessible to other family members and future generations.


GENES AND INHERITANCE: UNDERSTANDING THE BASICS

DNA (deoxyribonucleic acid) is a chemical that is the most basic unit of genetic information. Chromosomes are highly organized structures containing DNA in long strands (see illustration). Most cells in our body contain a complete set of 46 chromosomes, or 23 pairs. The chromosomes are numbered 1-22 (largest to smallest) and the twenty-third pair are the sex chromosomes, which determine our gender (two "X" chromosomes = female; one "X" and one "Y" chromosome = male). We inherit our chromosomes at the time of conception: one set of 23 from our mother and one set of 23 from our father. As we grow from a single cell into a complex human being, our chromosomes are copied into each new cell.

Genes are specific subunits or groups of DNA along the chromosomes. Just as our chromosomes come in pairs, so do our genes. Each gene codes for a protein (or chemical) that has a specific function in the body.

The following analogy may be helpful: One can think of a gene as a long word. Every letter in the word is a piece of DNA. Just like words, genes must be correctly "spelled", or have the correct DNA code in order to function properly. There are two types of "misspellings" that can occur in our DNA.

* One type includes words with multiple spellings but with the same meaning or a misspelling that is silent and allows the word to still be read correctly. For example, the word "theater" is sometimes spelled as "theatre". Despite this alteration you still understand the word and its meaning. This type of alteration in the DNA code is called a polymorphism.
* The second type of misspelling involves changes to the word that alter the meaning or make the word unreadable. An example is if the word "good" were changed to "gxod". One would not be able to make sense out of "gxod". This type of misspelling or change in the DNA code is called a mutation. Mutations alter the function of the gene and are often associated with disease.

Inherited conditions can be passed on (inherited) in families in different ways.

Autosomal dominant conditions affect males and females equally, and only one gene of the pair needs to be abnormal for the individual to have the condition. Every child of an individual with an autosomal dominant condition has a 50% chance of inheriting the mutation and having the disorder (Huntington's disease and achondroplasia (a common form of dwarfism) are examples of autosomal dominant conditions.) When examining a family history for an autosomal dominant condition, often times one will identify multiple individuals in each generation with the condition. It is important to understand that if an individual did not inherit the abnormal gene then he/she cannot pass it on.

- Features of Autosomal Dominant Inheritance: The condition appears in multiple individuals in multiple generations, and each affected individual has an affected parent. Any offspring of an affected parent has a 50% risk of inheriting the condition. Non-affected individuals do not transmit the condition to offspring. Males and females are equally likely to have the condition.


THE GENETICS OF FTD

TD can be sporadic, familial, or hereditary.

In the majority of cases, FTD is sporadic, meaning it is a disorder that develops in that person by chance rather than being inherited. When FTD is diagnosed in a patient with no family history of FTD or dementia, it is an isolated (sporadic) case, which appears to pose minimal (if any) elevated risk to family members.

Approximately 20% to 50% of patients have a positive family history for FTD or a related neurodegenerative condition or dementia (e.g. Alzheimer Disease, Parkinson Disease, or ALS). This may indicate that there is a predisposition for this type of neurological disease in the family, and that members of the family may be at increased risk to develop one of these disorders. The term "familial" is used to describe this unspecified, but likely increased, risk in relatives. In such a family, a meeting with a genetic counselor, who will take a detailed family history and discuss the possibility of such a risk, may be informative.

Only about 10% of FTD patients have a family history that suggests a hereditary condition with an autosomal dominant pattern of inheritance. This means there is a clear pattern of FTD-type diagnoses being passed from parent to child, with virtually every patient having an affected parent and each child of an affected person having a 50% chance to inherit the disorder

In cases of familial and inherited FTD the age of onset can be younger than those with sporadic presentations (thirties, and forties for familial FTD), and it is not uncommon for the condition to progress more rapidly. (A similar profile has been observed in a subset of Alzheimer patients, and dubbed "familial Alzheimer's".)

For several years researchers have been collecting blood and tissue samples from individuals whose symptoms and family history suggest that their disease has a significant genetic component (either autosomal dominant or familial), to try to determine the specific genetic cause for this group of diseases. This has enabled scientists to identify the fact that, in the majority of families with a hereditary pattern of FTD, the disorder is caused by a mutation in one of two specific genes. These genes are called MAPT and PGRN.

The MAPT gene is located on chromosome 17, and codes for the protein called tau. Abnormal amounts of the tau protein have been described in neuropathology (brain tissue) investigations among individuals with FTD, Alzheimer disease and other neurodegenerative conditions.

The families that were originally linked to the MAPT gene were given a more specific diagnosis called frontotemporal dementia with parkinsonism (FTPD-17). This condition was clinically described by the presence of dementia and/or parkinsonism, frontal and/or temporal atrophy of the brain, as well as two or more similarly affected family members consistent with an autosomal dominant pattern of inheritance. Scientists estimate that approximately half of the hereditary FTD families have a mutation in the MAPT gene.

More than 50 families have been found to have mutations in the MAPT gene. Many of these families have "unique" mutations that have only been described once. However, there are a few mutations that have been seen in multiple families around the world. In such cases, where the same mutation is seen in different families, specific phenotypic (clinical) features have been compared. These types of studies are called genotype/phenotype correlations. Such information can be useful for counseling families about the associated clinical findings and prognosis when a known mutation is identified. For example, some mutations are associated with a more rapid progression of the condition.

Many polymorphisms (genetic changes) have been described in the MAPT gene that are not directly linked to disease, although there are some specific patterns of polymorphisms, called haplotypes, that have been implicated by association with FTD. Researchers are currently trying to determine how specific haplotypes may modify risk for FTD. Studies of individuals with sporadic FTD have not yielded mutations in the MAPT gene.

In July, 2006 two different research groups published the finding that mutations in the PGRN gene are responsible for causing FTD in another approximately 5% of families; so together, the MAPT gene and the PGRN gene appear to be the cause of FTD in the majority of families with hereditary FTD.

The PGRN gene (also located on chromosome 17) contains instructions that tell cells how to make the protein progranulin. Progranulin is the precursor of a factor that stimulates cell growth and wound repair, and 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 not yet known, but in October, 2006 AFTD awarded a research grant to a group of scientists to develop a mouse model to investigate this question.

Although more studies need to be conducted on patients with a PGRN mutation, early results indicate that this population has a higher chance of developing progressive aphasia (one of the language disorders known to occur in some FTD patients) and are less likely to have motor neuron disease than are FTD patients without a PGRN mutation.

Michael Hutton, PhD., who leads one of the groups of scientists who made this discovery (and is on the AFTD Medical Advisory Council) adds the following thoughts: "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." (For more information on the PGRN research finding and a Q&A on the impact of this finding for FTD patients and families, follow this link:
http://www.ftd-picks.org/?p=research/200608_ResearchAdvance

In 2007 there have also been several research papers published regarding a handful of other genes that may be involved in various FTD subtypes. Research continues to investigate links between some FTDs and ALS (Lou Gehrig's disease) and some FTDs and Alzheimer Disease. There are also several families in which researchers may have found a unique genetic mutation that causes FTD in their specific family. All of this data provides tantalizing clues, but none of it is yet ready to be applied to patient care.

In the future genetic research will:

* Discover more mutations in the MAPT gene and therefore the clinical features associated with FTDP-17 will expand;
* Identify genotype/phenotype correlations that will be useful in providing genetic counseling to families;
* 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.
* Perhaps find additional FTD-associated genes (such as MAPT and PGRN) which will help researchers further understand the cause and biology of the FTDs.



GENETIC COUNSELING AND GENETIC TESTING

Genetic counseling is a communication process between an individual (or the family) and a healthcare provider with special training in genetics. Some of the activities in a typical genetic counseling session are:

* Construction of a family history and analysis of that history for patterns of inheritance and genetic risk;
* Education about natural history, genetics and inheritance of a condition;
* Discussion of recurrence risk for inherited and multifactorial conditions;
* Discussion of benefits and limitations of genetic testing; and
* Psychosocial support for individuals and families coping with a diagnosis.

A genetic counselor can also be an important ally in advocating health care needs for patients and families.

Genetic testing can be extremely complex. Not all tests are 100% diagnostic, and often there are ethical and social concerns that influence one's decision to have or not to have genetic testing. Genetic testing for FTD has been offered on a research basis mostly to individuals with a suspected familial or hereditary FTD. There is an important distinction between research genetic testing and clinical or commercial genetic testing. Research testing is not a diagnostic test: There is no guarantee of a result that will be of benefit to the patient. The goal of research testing is to advance scientific knowledge about the condition. This research is usually conducted in academic laboratories. A study coordinator or physician should review the details of the study and obtain informed consent from the patient and/or family members for participation. You should be provided with an informed consent form that has been approved by an Institutional Review Board (IRB) at the university or hospital where the research is being performed.

In contrast to research testing, clinical or commercial genetic testing involves a diagnostic test: The patient will receive an official result from the test. The testing is performed in a laboratory that has been approved for this type of diagnostic testing, to ensure the integrity of the result. Such laboratories are located in hospitals, universities, biotechnology companies and commercial laboratories. Often, clinical genetic testing is only offered after the patient and family have received genetic counseling to explore the benefits and limitations of testing.

In the near future clinical genetic testing will be available for diagnosis of individuals with or at-risk for hereditary forms of FTD. However, these tests will not be useful to all individuals. For example, genetic testing to identify disease-associated mutations in the MAPT or PGRN genes will only be recommended to individuals with a dominant family history of FTD. As more causative genes for FTD are identified, research testing will move to the clinical arena, further expanding the role of genetic testing for diagnosis of FTD.

Many individuals who are presently asymptomatic but believe that they are at increased risk for FTD based on family history have expressed an interest in genetic testing so that they can learn if they "inherited the gene". Pre-symptomatic or predisposition genetic testing is not a new concept in coping with neurodegenerative conditions. Such testing has been offered to individuals at risk for Huntington's disease, familial Alzheimer Disease and other genetic conditions. For the vast majority of these conditions, FTD included, there is no treatment. Therefore, an individual who has the pre-symptomatic genetic testing may learn that he/she is destined to have a progressive, debilitating disease, and that current medical knowledge cannot prevent this. Obviously, such information can be devastating to the individual. For this reason, genetic counseling before the test is performed is critically important. Many clinical centers and laboratories require that the individual go through a formal protocol of pre- and post-test genetic counseling along with psychiatric evaluation.

During genetic counseling, the individual will have an opportunity to discuss his/her motives for testing, to explore the possible result outcomes and their anticipated reaction and coping strategies for each, to develop a support system, and to discuss the risks associated with receiving a diagnosis (such as adverse psychological outcome, insurance or employment discrimination). The genetic counselor will also work to document the specific genetic abnormality or mutation in an affected family member, to confirm the diagnosis before testing other at-risk individuals in the family. (If a genetic mutation is not known in the affected family member, testing in other relatives will most likely be uninformative.) Genetic testing for untreatable conditions is not recommended for at-risk children because they are not able to provide informed consent and giving a child a "label" may do great harm.

Genetic counselors have Master's level training in human or medical genetics or genetic counseling and are certified by the American Board of Genetic Counseling. To locate a genetic counselor who specializes in FTD, contact your local University-based FTD or Dementia program. If this is not feasible, consult with your clinician or contact the National Society of Genetic Counselors via the internet at http://www.nsgc.org and go to the Resource Link to identify someone near you.



DISCUSSING THESE ISSUES WITH YOUR FAMILY

Genetic issues present a difficult dichotomy within a family. Your genes are what make you unique: no one else in the world has the same exact combination of genes that you do. Yet, you share 50% of your genes with each of your first-degree relatives (parents, siblings, and children). So any genetic issue is both extremely personal and common to all blood relatives.

For this reason, discussing genetic risk can be extremely difficult, even within the most supportive families. When the disorder in question is an adult-onset, progressive, neurological disease like FTD, the issues can be even more complicated. The patient's siblings are often raising their own families, and at the prime of their careers. The patient's children may be too young to understand genetic issues, may be considering marriage and a family of their own, or may already be raising their own children. None of these individuals will want to hear that they might be at risk for the disorder that is afflicting their loved one.

What can a caregiver do regarding communicating potential genetic risk to family members? To what extent is this your responsibility? While there is no one answer for every circumstance, here are some general guidelines and tools to help.

* Meet with a genetic counselor or have a serious discussion with your neurologist about the patient's family history and the likelihood that FTD might be inherited in the family. This is especially important if you have a high level of concern based on family lore about older relatives. This professional can help separate fact from "fiction" and, if there is valid reason for concern, they will devise a plan to get more information.
* If the patient's children are under age 18, there is no rush to have the discussion. Because FTD does not present a risk this early in life, no clinician would perform a genetic test on a minor; the policy is to test only adults who can understand the complicated issues involved and thus give truly informed consent. As with all complex, emotional issues, it is best to follow a child's lead, letting them know that you welcome their questions and making a judgment call as to how much information they are ready to know at any given time.
* Broach the subject with adult members of the immediate family. Chances are that if there is some family history, these people have been wondering about heritability, but not wanted to broach the subject themselves. Perhaps they are worried about appearing to have selfish concerns about the future, when you are dealing with the daily demands of your loved one. Opening the door to the topic will give them permission to pick up on the discussion, if they want to.
* There are different ways to introduce the topic. You could share copies of a letter from the neurologist that outlines the possibility that FTD is being inherited in the family. Use the exercise of researching the family history to introduce the topic with relatives who may have more information about ancestors. Share this booklet. Remember, it is OK that you do not have the answers to all of the questions; often it can be comforting just to know that others in the family have the same concerns.
* People within the family may react very differently to the subject. Some will want to talk about it; others may be scared and get angry. This is normal, and you should remember that they are not reacting to you, but to the threat of FTD. The best you can do is to let them know that there is a support network, and professionals who can help them find answers if and when they want to.
* Different members of the family will choose different paths to address this risk. Some will ignore it; some will want to discuss it with family; still others will pursue professional advice in private. It is important to know that a geneticist or genetic counselor will hold each individual's consultation in the strictest confidence. Information is not shared with other family members without an individual's consent.

You may not know which course each of your relatives takes. All that is important is for you to know that you opened the door to let each of them address it in his or her own way.



REFERENCES

Farmer, J. "The Role of Genetics: A Piece in the FTD Puzzle" (2003). What If It's Not Alzheimer's? (L. Radin, G. Radin, eds). Amherst, New York. Prometheus Books.

Farmer J, Grossman M. (2005) Frontotemporal Dementia: An Overview. Alzheimer's Care Quarterly. 6:225-232.

Goldman JS, Farmer JM, Van Deerlin VM, Wilhelmsen KC, Miller BL, Grossman M. (2004) Frontotemporal Dementia: Genetics and Genetic Counseling Dilemmas. The Neurologist. 10: 227-234.



FOR MORE INFORMATION

* What If It's Not Alzheimer's?, A Caregiver's Guide to Dementia, Lisa Radin and Gary Radin, editors, Prometheus Books, 2003. The first caregiver manual devoted exclusively to FTD, this valuable book is a wealth of information for patients and caregivers living with FTD. To order a copy, see www.prometheusbooks.com

* AFTD: www.ftd-picks.org

* National Society of Genetic Counselors: www.nsgc.org

* U.S. Surgeon General's Family History Initiative: www.hhs.gov/familyhistory