Understanding the Genetics of FTD a Guide for Patients and Their Families Acknowledgements

Understanding the Genetics of FTD A guide for patients and their families Acknowledgements

The authors wish to acknowledge the following centers and associations which contributed to the creation of this booklet:

v The University of Pennsylvania Center for Neurodegenerative Disease Research v The University of Pennsylvania Frontotemporal Degeneration Center v The Association for Frontotemporal Degeneration

This booklet was created by the University of Pennsylvania Center for Neurodegenerative Disease Research.

© 2012 by the Trustees of the University of Pennsylvania. All rights reserved. No part of this publication may be reproduced without permission from the Trustees of the University of Pennsylvania. 1 Frontotemporal

Frontotemporal degeneration (FTD) is one of the most common forms of dementia in individuals under the age of 65 years. Symptoms of FTD are caused by the progressive loss of nerve cells (neurons) in mainly the frontal and temporal regions of the brain, although other regions can be affected in some cases. The frontal lobes of the brain are involved in a number of functions, including personality, behavior, planning, reasoning, judgment, impulse control, and motor functions. The temporal lobes of the brain are involved in language, memory, and speech. Despite many years of research, it is still not known what triggers the process of neurodegeneration (neuron cell death) in the brains of people who develop FTD. However, clues are gleaned from the presence of particular protein accumulations inside the diseased neurons. In a subset of patients, the root cause of those protein accumulations can be found in the individual’s genetic code.

Symptoms

FTD is characterized by progressive decline in behavior and/or language with an average age of onset in the mid-50s to 60s. The clinical presentations of FTD can include: v Behavior: changes in personality, loss of empathy, apathy, inappropriate social behavior, and poor judgment v Language: problems with expression of language or problems with word meaning 2 Pathology

or any form of neurodegenerative Fdisease, the final and definite diagnosis is made at the end of life by “inclusions.” The second group is doing a brain autopsy. The autopsy will characterized by inclusions of a protein examine the location and severity of known as TDP-43. TDP-43 is also a major brain tissue loss (atrophy) as well as disease-associated protein found at perform detailed microscopic exam - autopsy in the brains of patients with inations to detect the types of abnormal amyotrophic lateral sclerosis (ALS). A protein accumulations in the brain. In small percentage of FTD is found to have FTD, an autopsy can usually distinguish a third protein, the FUS (fused in sarcoma) between two main types of pathology. protein, as the characteristic finding at One group is characterized by clusters autopsy. In most patients with FTD, the of tau protein. Tau plays an important role autopsy findings will pinpoint one of in the structure and function of a healthy these proteins as the primary finding, but neuron, but in some forms of FTD, sometimes, especially in older patients, the tau protein begins to stick to itself there may be an accumulation of more and accumulates, eventually forming than one type of protein, including large clumps. These clumps are called proteins that are associated with other neurodegenerative diseases, such as Alzheimer disease. Research is currently focused on Parietal Lobe under standing why and how Frontal Lobe these proteins accumulate, in hopes that the answer will lead Occipital Lobe to the development of FTD- Temporal Lobe specific therapies.

Emotions Cerebellum Judgment Personality Memory Language Treatments Since the causes of FTD are unknown, there is no way to prevent it, slow down disease v Movement: decreased movement, muscle rigidity, progression, or cure it. However, parkinsonism (tremor, problems with gait and physi cians may use medications balance), or motor neuron disease/ amyotrophic and treatments used in similar lateral sclerosis (Lou Gehrig’s disease) disorders such as Alzheimer disease or psychiatric illnesses to help v Executive: difficulty with planning, judgment and manage some of the symptoms. working memory 3 TYPES OF FTD

Type of Clinical Description of Type of Pathology FTD Description Possible Symptoms Seen in Brain

Behavioral Changes in 3 Hyperoral (ex. eating only sweets Associated with tau variant FTD personality, or a certain type of food) or AD pathology (bvFTD) emotions, and/or 3 Disinhibited actions (ex. making behaviors inappropriate comments) 3 Apathy, lack of motivation to do things 3 Lack of Insight (unaware of the impact of symptoms on others) 3 Impaired decision-making

Nonfluent or Deterioration in 3 Hesitant, effortful speech Most frequently tau agrammatic the ability to 3 Comprehension of the speech of protein pathology primary produce speech others may be preserved in early found progressive stages aphasia (PPA) 3 Typically lack features of bvFTD

Semantic Deterioration in 3 Difficulty naming objects or Most frequently TDP- variant PPA the ability to recognizing the meaning of the 43 protein pathology understand words word that names an object found and recognize 3 May have difficulty recognizing objects. familiar objects and faces 3 Fluent speech usually preserved

Logopenic Deterioration in 3 Speech can be slow due to Most often variant PPA the ability to difficulty finding the right words associated with retrieve words in 3 Able to understand word meaning Alzheimer disease speech (AD) pathology

Corticobasal Involuntary 3 Apraxia or difficulty with use of Associated with tau syndrome movements tools or AD pathology (CBS) and/or cognitive 3 Executive or social deficits dysfunction 3 Cognitive problems such as difficulty with simple math calculations and difficulty orienting objects in space

Progressive Deterioration of 3 Hallmark feature is inability to Tau protein supranuclear gait and balance; move eyes up and down palsy (PSP) eye movement 3 May also have other features of abnormality FTD subtypes

FTD with Same changes 3 Any symptoms associated with TDP-43 protein amyotrophic seen in other bvFTD or PPA lateral subtypes of FTD Features of ALS can include: sclerosis accompanied by 3 Muscle weakness & atrophy (FTD/ALS) deterioration of 3 Muscle cramps the motor 3 Difficulty swallowing neurons (also 3 Slurred speech sometimes called FTD/MND)

Pick’s A historic term for 3 Any symptoms associated with “Pick bodies” disease FTD, named for bvFTD or PPA (see above) consisting of tau Dr. Arnold Pick protein

4 FTD & Genetics

Genetics plays an important role in helping to better understand FTD. Even before genetic causes of FTD were first identified, doctors recognized that in some families, there was a history of multiple family members all being affected by a similar set of symptoms. These families and their participation in genetic research provided the first insights into understanding the hereditary forms of FTD. For the majority of patients with FTD, there is no family history of the disease and genetics is of little concern. However, for those individuals that do have concerns about the role that genetics plays in FTD, it is important to understand not only the specific genetic causes of FTD, but also the basic science behind why and how genes impact the risk and causes of human disease.

5 Genetics 101

ur genetic material, DNA, is stored proteins. Proteins are molecules made up Oin every cell of our body. A DNA of a chain of amino acid building blocks. chain is made up of individual units called Proteins are used by the body for nucleotides (an alphabet of 4 letters). maintaining its structure and function. DNA chains are then packaged into larger Because our cells have two copies of units called chromosomes. Individuals every autosomal chromosome, this have a total of 46 chromosomes. means we have two copies of each gene. Chromosomes come in pairs, and in each There are many different genes present pair, one chromosome comes from the on each chromosome. Both the sequence father and the other from the mother. The of the DNA and the number of copies of first 22 pairs of chromosomes are the each specific gene are important in same in males and females (known as maintaining normal function of the autosomes), whereas the 23rd pair human body. determines our sex (males, XY and A mutation is a change in the DNA females, XX). sequence; in other words there is a Genes are specific segments of DNA that spelling mistake or typo in the carry the instructions for making instructions to make a protein. When a proteins. The instructions are made up of mutation occurs in a gene, that copy of a unique string of nucleotides that the the gene has the wrong instructions to cell knows how to read and translate into make the protein and therefore it may

Chromosome

Cell DNA Molecule

Gene

Nucleus Protein

Our entire genetic code is stored in each cell of our bodies. The DNA is packaged in units called chromosomes. A gene is a specic section of DNA that contains instructions for building a protein.

6 make a protein that does not function changes are not harmful, they are just correctly in the body or is not produced in normal variations in the genetic code. sufficient quantity. There are many These normal variations are called different types of gene mutations. For polymorphisms and they are what make example, a mutation can occur because each of us look and behave differently. one or more nucleotides that encode Sometimes a variation in the DNA (spell) the gene is either changed, sequence is identified that has never been inserted, or deleted. In some cases the seen before so it can’t be classified as insertions and deletions can be large, even being harmful (mutation) or normal involving the whole gene. In another (polymorphism). There are tools and type of mutation, a region of DNA rules that researchers and doctors can use that normally has a small number of to evaluate these variations, but even so, a repeated sequence is abnormally sometimes a clear answer is not possible. expanded to have too many repeats, In these cases the changes are “inde - therefore affecting the function of nearby terminate” and are often referred to as genes. variants of unknown significance (VOUS). When a test result is indeterminate, The sequence of DNA in any individual is more work is needed to help determine determined using a variety of methods whether or not that change will have a collectively called “molecular biology.” Not negative effect. Studying additional family every change identified in the DNA is members can sometimes be helpful. automatically considered to be a disease- causing mutation. Some identified DNA

Mutations are Genetic Spelling Mistakes

When a gene is spelled correctly, the body is able to read the DNA letters in groups of three, similar to how we group letters to form words and sentences. If the gene is written correctly, the body can read the instructions.

Correct Gene Code Gene: ATC CAG AAT TAC Sentence: BUY THE RED CAR

A mutation changes the type or order of DNA letters. In the example below, one of the DNA letters changed from a C to an A. This changes the word, and thus the instructions change as well.

Incorrect Gene Code Gene: ATC CAG AAT TAA Sentence: BUY THE RED CAT

7 Genes & Family History

ost cases of FTD are sporadic, ancestry, family history, and the type of Mmeaning that there is no known FTD (see table “Types of FTD.”) Clinically, family history of FTD. In some cases there both inherited and sporadic FTD exhibit is not enough information known about the same symptoms, which makes the neurological health of the family evaluation of the family history the most members to rule out a possible genetic sensitive tool for determining the component; this situation may be likelihood of a genetic cause. referred to as a family history of unknown As seen in the pie chart image, families significance. While a very small per - that include a history of multiple relatives centage of families that appear to be of with FTD and/or ALS are the most likely sporadic origin or those that have family to have an underlying genetic cause, histories of unknown significance may in while cases with sporadic or unknown fact have a detectable genetic cause, the family histories are the least likely. There vast majority of gene mutations are are also families that fall in the middle, found in cases with a family history of meaning that there is at least one relative neurodegenerative disease. who has or had a related neuro- Approximately 40% of individuals with degenerative disease like Alzheimer or FTD have a family history that includes at Parkinson disease, but not a clear-cut least one other relative who also has or family history of FTD or ALS in close had a neurodegenerative disease. In relatives. In short, the greater the family approximately 15-40% of all FTD cases, a history of FTD or an associated disease genetic cause (e.g. a gene mutation) can like ALS, the more likely genetics plays a be identified as the likely cause of the role. It is important to note that not all disease and in most cases it is an individuals with a family history of inherited mutation. The gene mutation neurodegenerative disease will have rate can vary due to factors such as an identifiable gene mutation. This could

Strong Strong family history family history of FTD and/or ALS of FTD No mutation identified and/or ALS Some family history of Gene neurodegenerative mutation disease Gene mutation

Sporadic or Legend unknown Strong family history of FTD and/or ALS: Accounts Some family history of family history for about 10-15% of FTD. The majority, but not all, neurodegenerative have a mutation in a currently known FTD gene. No mutation identified disease No mutation Some family history of neurodegenerative disease: identified Accounts for about 20-25% of FTD. Less than half have a mutation in a currently known FTD gene.

Sporadic or unknown family history: Accounts for about 60-70% of FTD. Only a small percent (less than 10%) Sporadic or have a mutation in a currently known FTD gene. unknown family history Gene mutation 8 Autosomal Dominant Inheritance Legend Parent Gene Mutation Generation No Mutation be because the responsible gene has not yet been identified, or because the disease is Offspring not actually due to a Generation gene mutation. The Did not inherit Did not inherit Did inherit Did inherit specific genes that have mutation mutation mutation mutation been associated with This diagram shows all the possible inheritance combinations for a couple in which one parent has a gene mutation and the other parent does not. Each time the parent with FTD are discussed in the gene mutation has a child, there is a 50% chance of passing on the copy of the gene with the mutation, and a 50% chance of passing on the copy without a mutation. detail in the next The chances are equal for males and females. section. There are many descrip tive words used in inheritance means that only one copy of the medical setting when discussing a gene has to have a mutation to cause family history. These words are often used disease. Typically, the copy of the gene interchangeably, making it potentially with the mutation is inherited from a confusing to understand each term’s parent, and most individuals with an meaning and significance. For example, autosomal dominant condition will have the term “hereditary” indicates that a trait a family history of the disease. A child of or disease can be directly transmitted a person with a dominant mutation has a between parent and offspring. “Familial” 50% chance of inheriting the copy of the is a very broad term used to indicate that gene with the mutation and a 50% more than one person in a family has a chance of inheriting the copy of the gene trait or disease. “Familial” denotes that without the mutation. there is a possibility of a genetic cause At this time, the only proven genetic due to apparent clustering of affected causes of FTD fall under the pattern of individuals in a family. This may occur autosomal dominant inheritance. It is by chance or due to a genetic mutation believed that there are likely other (hereditary cause). When a genetic factors, both genetic and environmental, counselor looks at a person’s family that influence an individual’s risk of history and draws a pedigree, they look developing FTD. There may be genes or for patterns of disease in the family and specific mutations that do not directly depending on the number and type of cause FTD, but rather increase suscep - affected individuals, a “pattern of tibility to disease. This type of genetic inheritance” is assigned. finding is referred to as a risk factor. It is A classic pattern of genetic inheritance is also likely that a combination of both called autosomal dominant. “Autosomal” genetic and environmental factors refers to the first 22 pairs of chromo - influence the risk of disease; this is often somes, which are identical in both males referred to as multifactorial inheritance. and females. Therefore, both genders Research is underway to determine other have an equal chance of being affected if risk factors that play a role in the a mutation is present on a gene in an development of FTD. autosomal chromosome. “Dominant”

9 Genes Associated with Hereditary FTD

All of the genes described in this section can cause hereditary FTD and follow the autosomal dominant pattern of inheritance (see page 9).

C9orf72 – Found on Chromosome 9 • The genetic mutation on chromosome 9 was discovered in 2011, after many years of research. The function of the protein that C9orf72 codes for is not yet understood. Individuals with the C9orf72 mutation have abnormal accumulations of the TDP-43 protein in affected neurons. • The C9orf72 mutation can cause FTD, ALS, or a combination of both FTD and ALS. Research is ongoing to better understand how this mutation can lead to two different types of clinical symptoms. • The C9orf72 mutation is believed to be the most common genetic cause of repeats. The section of DNA is referred hereditary FTD, accounting for 5-20% of to as a hexanucleotide repeat, which all FTD cases. Most cases will have a means that 6 (hexa) units of DNA family history of either dementia or (nucleotides) are repeated to such an ALS, but a small percentage of C9orf72 extent as to negatively impact the cases may occur in apparently sporadic gene’s ability to create a functional cases. protein. • The clinical features of patients with FTD due to C9orf72 mutations are still Microtubule-Associated Protein being compiled, but initial reports Tau (MAPT) – Found on show: Chromosome 17 o Average age of onset is in the 50’s • MAPT, discovered in 1998, was the first (range 30’s to 70’s) gene found to be associated with o Wide range of symptoms and hereditary FTD. MAPT codes for the disease progression. Patients with protein tau and individuals with MAPT behavioral, language, and of mutations have abnormal accumu - course, ALS symptoms have been lations of the tau protein in affected reported in cases of C9orf72 neurons. mutations. • Mutations in MAPT account for 5-10% • The penetrance of C9orf72 is not yet of all FTD cases. People who have FTD fully understood, but it may have have due to MAPT will typically have a family reduced penetrance. history of other relatives affected by the • The mutation is an expansion, or disease; however, family history may be increase in size of a small section of unknown because of lost family DNA by increasing the number of members, early death, or adoption. 10 • Mutations in MAPT are associated with • There can be a wide range of a wide range of FTD subtypes including symptoms, disease progression, and bvFTD, semantic variant PPA, PSP, and age of onset both between families and CBS. The most common subtype within the same family. associated with MAPT mutations is • Reduced or age-dependent pene - bvFTD. trance has been reported. • Average age of onset is 52 years (range: 40-60). Valosin-Containing Protein (VCP) • Wide range of symptoms, disease • VCP mutations are associated with a progression, and age of onset both specific condition called inclusion body between families and within the same myopathy with Paget disease of the family. bone and FTD (IBMPFD). Inclusion body myopathy (IBM) is characterized by • Most cases reported have complete slowly progressive muscle weakness penetrance. beginning in the teens to early • Mutations in the gene are MAPT adulthood. Paget disease of the bone is associated with the clinical diagnosis of characterized by enlarged and mis - FTDP-17, which stands for FTD with shapen bones. parkinsonism on chromosome 17. The • VCP mutations account for a very small name arose because some, but not all, percentage of FTD cases, but only in patients with MAPT mutations also families with the specific constellation developed movement symptoms, such of symptoms as described above. as tremors or balance problems. • There is a wide range of symptoms, Progranulin (GRN) – Found on disease progression, and age of onset Chromosome 17 both between families and among • GRN was discovered in 2006 and codes families with a VCP mutation. Affected for the protein progranulin. Individuals individuals may develop FTD, IBM, with GRN mutations have abnormal Paget disease of the bone or any accumulations of the TDP-43 protein in combination of the three conditions. affected neurons. Other genes associated with rare • Mutations in GRN account for 5-10% of FTD cases: all FTD cases. People who have FTD due to GRN will typically have a family Charged multivesicular body protein 2B history of other relatives affected by the (CHMP2B) disease; however, family history may be • Extremely rare cause of FTD, only unknown because of lost family found in a few families world-wide members, early death, or adoption. TAR DNA-binding protein (TARDBP) • GRN mutations are associated with a • Mutations in TARDBP are very rare. wide range of FTD subtypes including These mutations are more commonly bvFTD, nonfluent variant PPA, and CBS. associated with hereditary ALS than Similar to MAPT mutations, bvFTD is the FTD. most common subtype associated with Fused in sarcoma (FUS) GRN mutations. • Mutations in FUS are very rare. These • Average age of onset is 59 years (range: mutations are more commonly 35-87 years). associated with hereditary ALS than FTD. 11 Genetic Testing

months to complete. Some insurance companies cover the costs, but policies vary regarding coverage and reim - burse ment for genetic testing services. Costs of clinical genetic testing can vary from a few hundred dollars to over a thousand dollars. The results of the clinical test would be reported back to the individual, as well as the doctor who ordered the test, so that the results can be recorded in the patient’s medical record. enetic testing for FTD is performed Many FTD research centers conduct Gby analyzing a DNA sample for genetic research studies in which indi - changes in the genes known to cause viduals can participate; however, policies FTD. This process is similar to the concept vary regarding whether or not results of spell-checking a document to make from research tests would be returned to sure everything is correct. The DNA the individual. When participating in a sample is typically obtained from blood, genetic research study, it can be helpful but sometimes other sample types, such to ask whether or not results are ever as saliva or tissue from an autopsy can be shared with participants. If results are used as the source. These sample types shared with participants, ask when and may be used if blood cannot be obtained, how results might be communicated; and autopsy tissue can be useful for often research testing takes much longer testing a deceased affected family to conduct than clinical testing. member. Clinical genetic testing is available for all of the genes The difference between clinical & research testing associated with hereditary FTD, Testing Testing as well as many of the genes

associated with rare FTD cases. Diagnosis or risk Scientific knowledge information and discovery of To obtain a clinical genetic test, treatments

a doctor orders the test from a CLINICAL RESEARCH clinical laboratory that is licensed and certified to pro - Results given Results given to patient to researcher vide clinical genetic testing services. Testing of the sample Cost to the Cost to the by a clinical lab is usually done patient researcher Kept in patient’s Kept in researcher’s in 1-2 weeks, although in some medical record records cases it may take up to 1-2 12 If an individual definitely want the results possibility that there is a gene mutation of the genetic testing, it would be responsible. Not every individual with a advisable to first look into clinical genetic family history of disease will have a testing, as this provides a guarantee of detectable mutation, but it does provide receiving results. some insight regarding the possibility. There is a much lower likelihood of Family history provides the biggest clue finding an FTD gene mutation in a as to whether genetic testing might sporadic family pedigree; however, detect a disease-causing mutation. sometimes mutations are found in Typically, the stronger the history of patients that do not have a family history dementia and/or movement disorders in suggestive of hereditary disease. There other family members, the greater the (cont’d. on page 14)

The Concept of Penetrance

Penetrance refers to the proportion of individuals with a mutation in a particular gene who will actually develop symptoms of the disease.

Gene mutation & symptoms Gene mutation but no symptoms

Complete penetrance occurs Reduced penetrance occurs when every individual with a when some individuals with a gene mutation develops gene mutation develop symptoms of the disease symptoms of the disease while others do not

Penetrance is an important concept to Reduced penetrance occurs when some review in order to better understand the individuals with a particular gene muta - genetics of FTD. It is a term used to refer tion do not develop symptoms of the to the likelihood that a mutation in a disease. Sometimes the term “age- particular gene will result in a disease. dependent penetrance” is used in FTD. Complete penetrance occurs when every This means that, for an individual with individual with a particular gene muta - a gene mutation, the likelihood of tion develops symptoms of the disease. symptom onset increases with age. 13 Genetic Testing (continued)

are a few reasons why this may occur. risk of developing other symptoms, such Other relatives that had the mutation as symptoms of ALS in C9orf72 may have died of an unrelated cause mutations. The detection of a mutation prior to ever developing symptoms of would also determine the risk to other FTD. Sometimes patients are not aware of family members for inheriting the same medical information on more distant gene mutation. At the time of this relatives that might have been affected publication, there is not a specific and an assumption is made that no one medication or treatment that would be else was affected. In many families, it can given to a patient based on the results of be difficult to get accurate medical a genetic test; however, the results may information on aunts, uncles, and grand - prevent the patient from getting parents. Sometimes, it is not possible to additional, unnecessary testing or get any family medical information prevent treating the patient for the because the affected indi vidual was wrong diagnosis. As the field of FTD adopted or unsure of the identity of his research advances, patients with gene or her biological father. This is why some mutations might be candidates for new pedigrees are classified as “unknown treatment options or clinical trials for the significance” for genetic risk assessment. specific FTD subtype identified. Importantly, this does not mean a FTD gene mutation won’t be found, just that we don’t have enough information to Genetic Testing for Family assess and quantify the risk. Members of Individuals with Any patient with FTD has the option to FTD pursue genetic testing for the known FTD Once a disease-causing gene mutation genes, although a genetic cause is more has been found in an individual affected likely in those individuals who also have by FTD, this information can be used to a family history of FTD or other neuro - provide genetic testing services to other degenerative diseases. For specific individuals in the family. Affected family questions about genetic testing for FTD, members can be tested specifically for it would be best to speak with a clinician the known mutation to confirm its familiar with genetic testing, such as a presence. medical geneticist or genetic counselor. Unaffected family members who are at- risk of inheriting the mutation can choose to have presymptomatic genetic Genetic Testing for Individuals testing. Presymptomatic genetic testing with FTD refers to the idea of testing a currently If a mutation is found in a gene unaffected person to determine whether associated with FTD, the patient’s or not they have inherited a known gene diagnosis would be confirmed. In some mutation that has been found in their cases, it may provide insight into the family. This is also sometimes called progression of the disease, or even the predictive genetic testing. At this time,

14 Any patient with FTD

has the option to pursue

genetic testing for the

known FTD genes,

although a genetic

cause is more likely

in those individuals

who also have a family

history of FTD or other

neurodegenerative

diseases.

there are no preventative options every possible angle, such as exploring available for FTD and therefore the the potential impact of the results and decision to pursue presymptomatic the risks and benefits of testing for the genetic testing is entirely personal in person being tested, their relatives, and nature and can be a difficult decision to their significant others. It is also make. important to explore the motivations or reasons for learning the test result, as well The purpose of the presymptomatic as the limitations of knowing this type of genetic testing process is to provide a genetic information. Some clinics may structured, thorough, and supportive advise that the individual have a approach to the personal decision to neurology exam and/or a mental health learn one’s genetic status. In order to evaluation as part of the genetic testing accomplish this goal, presymptomatic process. genetic testing typically involves several visits. A genetic counseling session is The blood for the genetic test is drawn at conducted to discuss the testing decision a subsequent visit, allowing for a window in detail. Prior to learning one’s of time during which the individual can presymptomatic testing result, it is reflect and feel absolutely sure of his or important to consider the decision from her decision to learn their genetic result. (cont’d. on page 16) 15 Genetic Testing (continued)

The results are then disclosed during an Genetic Testing for Family in-person visit; not by mail or over the Planning Reasons telephone. Most centers require the The topic of family planning is immensely presence of a support person at this post- personal. For individuals with either a risk test visit. If the individual has not of inheriting an FTD gene mutation or inherited the mutation, he or she is not at individuals known to have a mutation, risk for the hereditary FTD that has there may be difficult feelings and affected other family members. The questions to face regarding starting a individual would have the same risk for family of their own. Often individuals neurodegenerative diseases (including are concerned about the risk of passing FTD) as the general population. If the the mutation on to their own children, individual has inherited the mutation, he the next generation of the family. There or she is at definite risk for developing are reproductive technologies, such as FTD at some point in her life. It is nearly preimplantation genetic diagnosis (PGD), impossible to predict the exact age of that have been developed to address this onset or the type of symptoms to expect, concern. In PGD, the process of in vitro but in some cases, the specific gene or fertilization (IVF) is used to develop gene mutation may provide some embryos. These embryos are then tested additional insight into the risk. for the known family mutation, and only embryos that did not inherit the mutation are used for implantation. PGD is only one example of available repro - ductive options. Other family planning options include gamete (egg or sperm) donation, adoption, natural conception, or the decision not to have children. There are clinicians, including physicians and genetic counselors, who specialize in providing pre - conception and prenatal genetic services. For indi - viduals that desire more information and support regarding family planning, it is advisable to schedule a consultation with such a professional.

16 Q&FAQs for FTDA Genetic Testing • • •

The following Q: Is there a genetic test for FTD? is a guide to A: Yes, clinical genetic testing is available to look for mutations in MAPT, GRN, VCP, TARDBP, C9orf72 and some of the FUS. A doctor or genetic counselor would be able to most provide more details about the specific genetic testing options that are most appropriate based on an frequently individual’s symptoms and family history. asked Q: How is the genetic test done? questions A: Blood or saliva is collected and used to isolate a about genetic sample of DNA. This DNA sample can then be testing for analyzed for mutations in the specific genes of interest. For individuals with an unknown genetic cause, a com - FTD. plete analysis for any known disease-causing genetic changes would need to be performed. However, for indi - If you have vi duals that already know the specific gene muta tion that is present in their family, the genetic test can be questions that targeted to just check for that known family mutation. are not addressed, Q: Who can get genetic testing? please contact A: Any individual with FTD who is interested in genetic testing may get tested, although a genetic cause a genetic is more likely in those individuals who also have a family history of FTD. Anyone considering genetic counselor or testing or who has a family history of FTD should seek other clinician genetic counseling prior to genetic testing. The test is most beneficial when a family member with FTD is the familiar with first person tested. Once a mutation has been identified, genetic other members of the family may choose to be tested for the same mutation even if they don’t have symptoms testing. of the disease (presymptomatic genetic testing). (cont’d. on page 18)

17 Q: What is genetic counseling? • Genetic testing methods may vary. For example, some tests only look for specific A: The goal of genetic counseling is to help mutations, whereas others look for any people understand more about the genetic Q&Aand all mutations in the gene. causes of a disease and how it may affect them so they may make informed • Not all genetic causes are known. decisions. Genetic counselors can explain Scientists are still working to find other how genetic conditions are inherited, genes that contribute to FTD. determine if an individual is at risk, Indeterminate: An indeterminate result provide options and guidance for genetic means that a change was found in the testing, and find referrals for other genetic sequence of the gene, but the resources. laboratory cannot yet make a clear determination as to whether it is a disease- causing mutation, a risk factor, or a Q: If I already have FTD, what normal polymorphism. Normal poly - would a genetic test tell me? morphisms are common variations in A: Genetic testing may help define the risk DNA that do not cause disease. An of FTD for other family members. There indeterminate result is sometimes called a are three possible types of genetic test variant of unknown significance. results: positive, negative, and inde - The interpretation of genetic test results can terminate. be confusing. It is recommended that Positive: A positive test result would anyone who has genetic testing for FTD mean that the individual has a disease- discuss the results with a genetic counselor causing mutation. A positive test result or another medical genetics professional. indicates that the cause of FTD observed in the family has been found. This would Q: If I have a family history of FTD, further define the risk for other family should I be tested even if I do not members to develop FTD and allow them have symptoms? to pursue presymptomatic genetic testing if interested. A: Testing a person who is currently not showing symptoms but who is at risk for Negative: A negative test result would inheriting a known family mutation is mean that the individual did not have a called presymptomatic (or predictive) mutation in the tested gene or genes. testing. For presymptomatic testing, a However, a negative result would not rule mutation must have been first identified in out the possibility of a genetic cause the family so that the clinician knows the entirely for the following reasons: appropriate test to order and can properly • Not all genes may have been tested. For interpret the results. Individuals in the example, some tests may look at only one same family may have differing opinions specific gene, whereas others may test on whether or not to pursue pre symp - multiple genes.

18 tomatic testing. The pursuit of pre - Research testing may also identify or test symptomatic testing is a very personal for new disease-associated genes before decision that may be confusing and they are available as a clinical test. emotionally difficult. Therefore, genetic Q: What are the risks that my child counseling and psychological evaluation will also get FTD? are usually required to help the individual throughout the testing process. A: If an individual has a mutation in one of the known FTD associated genes, there is a 50% chance of passing on the Q: What is the difference between mutation and a 50% chance of NOT clinical and research genetic testing? passing on the mutation to his/her child. This same 50/50 risk applies to every child A: The purpose of clinical genetic testing of that individual. If the child does inherit is primarily for diagnosis or prediction of the mutation, he or she will most likely disease. The testing is performed in an develop symptoms of the disease at some accredited laboratory. A report of the point in adulthood, but the age of onset, results is generated and will be part of the severity, and type of symptoms cannot be patient’s official medical record. There is a predicted at this time. charge for clinical testing, which may or may not be covered by insurance. Clinical (cont’d. on page 20) genetic testing does not help scientists discover a cure or new treatments for FTD and the results do not affect medical management at this time (because there are no approved treatments) . The purpose of research genetic testing is to discover and to better understand the genetic factors of FTD and how these impact the clinical presentation and pathology. In research, patient identifiers and information remain confidential and results do not become part of the patient’s official medical record. There is no fee when participating in a research study, and generally results are not returned to participants. Many individuals choose to participate in research genetic testing to help advance the FTD field for the benefit of future generations. Research genetic testing may lead to a better understanding of the causes of FTD and the development of better treatments or a cure in the future. 19 If an individual with FTD does not have a Q: If I have a genetic mutation, mutation in a known FTD gene and does what can be done about it? not have a family history suggestive of a A: At this time, we cannot change or alter Q&Ahereditary cause, the risk to children is much lower and is likely close to the an individual’s genetic make-up. There are general population risk, which is low. If an research studies looking into new individual with FTD does not have a technologies for treating genetic diseases, mutation, but does have a family history but this is currently not available as a suggestive of a hereditary cause, it would medical treatment for FTD. Identifying a be important for that family to get gene that causes FTD in an affected involved with an FTD genetic research individual will not provide an answer for study to try to determine whether a genetic curing the disease, but may help prevent cause or risk factor can be identified. This the patient from being treated for the information would be crucial for providing wrong diagnosis. Additionally, if an accurate information to individuals unaffected person finds out that they possibly at-risk. As with any human inherited a FTD gene mutation, there is no disease, there may be environmental or treatment available at this time to prevent genetic risk factors that could increase the onset of disease. susceptibility to a disease. At this time, there are no known risk factors that could Q: What causes a gene mutation? indicate a susceptibility to FTD, but ongoing research is working to better A: In FTD, most identified mutations are understand risk factors for FTD. believed to have been inherited, passed from parent to child throughout many generations. There is likely an ancient Q: Is there protection from genetic ancestor who was the first person to have discrimination? the mutation. In the genetics profession, A: The Genetic Information Nondis - this ancient ancestor is referred to as the crimination Act (GINA) was signed into “founder.” It can be very difficult to federal law in 2008. GINA provides legal determine why the mutation ever occurred protections against genetic dis crimination in the first place. Sometimes, there is a in health insurance coverage and matters region of DNA that is less stable and prone related to employment. GINA does not to mistakes (i.e. mutations) being made. provide protections for life insurance, long- Our bodies have a way to detect and correct term care insurance, or disability these mistakes, but sometimes not every insurance. Individuals who are considering mistake is corrected. Gene mutations due to genetic testing to determine if they are at environmental exposures can occur, but are risk for FTD are encouraged to learn more typically restricted to the exposed person about the protections GINA does and does and it is unlikely that the mutation could not provide, as well as any relevant state be passed to the next generation. Gene laws. (A guide to GINA is provided in mutations due to environmental factors “Helpful Links and Resources”.) have not been reported to cause FTD. 20 Q: If I did not inherit the FTD gene Q: Everyone has always said that I mutation that has been found in my look and act just like my mom, who family, could it still appear in my has been diagnosed with FTD. Does own children? this mean I’m more likely to also get FTD? A: If an individual has been tested for a mutation that is known to affect their A: Having a resemblance to a parent with family, and they do not have it, they are FTD does not increase the risk of also not at risk themselves for the genetic developing FTD. It can be very easy to disease and cannot pass it to their own assume that if we strongly resemble one of children. Sometimes people refer to the our parents, we are destined to share many idea of a disease “skipping a generation;” of their same fates. From a purely this is a common genetic myth. A truly biological standpoint, humans are a 50/50 genetic disease cannot skip through a combination of both parents’ genes, even family, as the only way to get the disease if a person cannot see that combination by is the direct inheritance of a disease- looking in a mirror. When it comes to causing mutation from parent to child. FTD, the only known genetic causes are There are several reasons a genetic disease inherited in an autosomal dominant may appear to skip a generation, even manner. In this type of inheritance, there though the mutation itself does not skip a is a 50% chance of inheriting the copy of generation. For example, sometimes an the gene with the mutation, and a 50% individual may pass away from an chance of inheriting the copy of the gene unrelated cause before ever developing without a mutation. There is also no sex symptoms of the disease. Also, some effect, in that sons are not more likely to mutations do not always result in disease inherit the disease from their father, nor because of reduced penetrance (see page are daughters more likely to inherit the 13). In both of these scenarios, the person disease from their mother. carrying the mutation can still pass it on to the next generation.

21 Glossary of FTD and Genetic Terminology

Allele – Another word for gene. Sometimes used when referring to different versions of a gene. Amino acids - Small chemical units that link together to form a protein. Autosomal dominant – A type of inheritance in which only one copy of a gene pair needs to have a mutation in order for the trait or disease to present. Behavioral variant FTD (bvFTD) – The clinical term for an individual with behavioral and personality changes as the primary symptoms. C9orf72 – A gene of unknown function with a specific type of mutation, called a hexanucleotide repeat (a large repeat of a section of genetic material) that was recently discovered on chromosome 9. This mutation can cause hereditary FTD and/or ALS. CHMP2B – A very rare cause of genetic FTD, this gene makes the charged multivesicular body protein 2b. Chromosome – A unit of tightly wound and packaged DNA. Each chromosome has thousands of genes. Corticobasal syndrome (CBS) – An FTD-related diagnosis that typically first presents with motor symptoms, similar to Parkinson disease. The term corticobasal degeneration (CBD) is also used, but usually is reserved for the final autopsy diagnosis of this condition. DNA – Deoxyribonucleic acid. DNA is a long, double-stranded structure of genetic material. Frontotemporal degeneration (FTD) or Frontotemporal lobar degeneration (FTLD) – These 2 terms are used interchangeably to refer to a spectrum of disorders that cause progressive changes in personality, behavior, and/or language. FUS – The FUS gene makes the fused in sarcoma protein, which is believed to help support normal DNA functions. Mutations in this gene are a rare cause of genetic FTD. Gene – A unit of DNA that carries the instructions to make a specific protein. Genetic testing – The process of using laboratory techniques to analyze genetic material (DNA). GRN – see Progranulin Microtubule-Associated Protein Tau (MAPT) -The official name of the gene that makes the tau protein. Motor neuron disease – Also known as amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease. A progressive loss of the neurons that control muscle movement. 10-15% of patients with FTD may also develop symptoms of ALS, and the two disorders have been closely linked based on results of recent research advances. Mutation – A change in DNA that affects a gene’s ability to make a protein. May result in disease.

22 Nucleotide – An individual chemical unit; nucleotides are the letters that make up the spelling of DNA. In DNA, the nucleotides are A, T, G, and C. Parkinsonism – A term used to describe motor symptoms that are similar to those seen in Parkinson’s disease, such as tremors, stiffness, and walking/balance difficulties. Penetrance – The likelihood that a genetic mutation will result in disease. Pick’s disease – An old diagnostic term for FTD, named for the physician that first described the condition. It is also used as a pathological diagnosis for some types of FTD. Polymorphism – A normal variation in the DNA code. In contrast to disease gene mutations, polymorphisms do not directly cause disease. Primary progressive aphasia (PPA) – The clinical term for an individual with language difficulties as the primary symptom. There are several different types of PPA, including semantic, non-fluent/agrammatic, and logopenic. Progranulin – The progranulin gene (GRN) makes the progranulin protein, which functions in cell growth and repair. Mutations in GRN cause hereditary FTD. Progressive supranuclear palsy (PSP) – A rare diagnosis related to both FTD and Parkinson disease that causes both cognitive and movement difficulties, including a characteristic difficulty with eye movements. Protein – A molecule that serves a specific function in the body. Proteins are made up of individual units called amino acids. Sequencing – A genetic testing method in which the letters of the genetic code are read nucleotide by nucleotide and then compared to the normal sequence in humans to look for differences or misspellings. TARDBP – The tar DNA-binding protein, also known as TDP-43, is made by the TARDBP gene. Mutations in this gene can cause genetic FTD. Tau –This protein is found in about half of FTD cases at autopsy. While not all FTD cases with tau protein are genetic, there are some cases of FTD that are caused by mutations in the gene that makes the tau protein (MAPT). TDP-43 – This protein is found in about half of FTD cases and almost all cases of ALS. The function of TDP-43 in the brain and it’s relation to neurodegeneration is not fully understood. Variant of unknown significance (VOUS) - a change in DNA that has an unknown clinical impact. VCP – The valosin-containing protein is made by the VCP gene. Mutations in this gene cause a specific condition called inclusion body myopathy with Paget disease of the bone and FTD (IBMPFD).

23 Helpful Links & Resources

Websites The Association for Frontotemporal Degeneration www.theaftd.org University of Pennsylvania Center for Neurodegenerative Disease Research www.med.upenn.edu/cndr National Society of Genetic Counselors www.nsgc.org The Coalition for Genetic Fairness: A Guide to the Genetic Information Nondiscrimination Act www.geneticfairness.org/ginaresource. html Genetics Home Reference http://ghr.nlm.nih.gov/ National Institute on Aging: Frontotemporal Disorders, Information for Patients, Families and Caregivers www.nia.nih.gov/alzheimers/publication/ frontotemporal-disorders-information- patients-families-and-caregivers

Books What if it’s not Alzheimer’s? A Caregiver’s Guide to Dementia (2008), edited by Lisa Radin & Gary Radin