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.