Dementia Dementia Dementia Definition Dementia also known as

Dementia

Dementia

Dementia: Definition • Dementia, also known as senility, is a broad category of brain diseases that cause a long term and often gradual decrease in the ability to think and remember • Significant enough that it affects a person's daily functioning • Other common symptoms include emotional problems, problems with language, and a decrease in motivation • A dementia diagnosis requires a change from a person's usual mental functioning and a greater decline than one would expect due to aging

Facts About Dementia • The most common type of dementia is Alzheimer's disease which makes up 50% to 70% of cases. • Other common types include vascular dementia (25%), Lewy body dementia (15%), and frontotemporal dementia • About 10% of people develop the disorder at some point in their lives • It becomes more common with age • About 3% of people between the ages of 65– 74 have dementia • 19% between 75 and 84 • Nearly half of those over 85 years of age

Alzheimer Disease • Early onset Alzheimer disease • More than 150 mutations of the presenilin-1 PSEN 1, presenilin-2 PSEN 2, and amyloid precursor protein APP genes have been associated with early onset disease • AD, autosomal dominant inheritance (one copy of the gene) • Late onset Alzheimer disease • Associated with APOE gene • E 4 increases your risk of developing late on-set Alzheimers • 1 copy increases your risk slightly • 2 copies of E 4 can be associated with memory loss over age 65 • E 2 protects you against effects of E 4 • E 3 appears neutral and is the most common allele/form of the APOE gene • It is important to note that people with the APOE e 4 allele inherit an increased risk of developing Alzheimer disease, not the disease itself • Not all people with Alzheimer disease have the e 4 allele, and not all people who have the e 4 allele will develop the disease

Lewy Body Dementia • Lewy Body Dementia refers to both Parkinson disease dementia and dementia with Lewy bodies, deposits of alpha-synuclein proteins in neurons in the brain • The earliest symptoms of these two diseases differ, but reflect the same underlying biological changes in the brain • Over time, people with both diagnoses will develop very similar cognitive, physical, sleep, and behavioral symptoms • Affected individuals are very sensitive to medicines used with Alzheimer and Parkinson disease

Other Forms of Dementia • Vascular dementia is caused by a series of small strokes that deprive the brain of vital oxygen • Symptoms, such as disorientation in familiar locations; walking with rapid, shuffling steps; incontinence; laughing or crying inappropriately; difficulty following instructions; and problems handling money may appear suddenly and worsen with additional strokes • High blood pressure, cigarette smoking, and high cholesterol are some of the risk factors for stroke that may be controlled to prevent vascular dementia • Frontotemporal dementia (FTD) includes several disorders with a variety of symptoms • The most common signs of FTD include changes in personality and behavior, such as inappropriate or compulsive behavior, euphoria, apathy, decline in personal hygiene, and a lack of awareness concerning these changes • Some forms of FTD involve language and speech symptoms or movement changes • One form is associated with the GRN (granulin) gene on chromosome 17 q 21 • Inheritance is autosomal dominant: one copy of the gene can cause this form of dementia • 95% of people have one affected parent

Genetic Testing for Dementia • Alzheimer Disease • Promethease • Analyzes 24 SNPs associated with the disease from various studies and APOE • 23 and. Me • Analyzes APOE and reports APOE 4 results only • Lewy Body dementia • No genetic testing available • Vascular dementia • Diagnostic tests include clinical diagnosis, imaging and blood work • Frontotemporal dementia (GRN) • Genetic testing may be available for this form

ALS Amyotropic Lateral Scelerosis or Lou Gehrig’s Disease

What Is ALS? • Progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, developing at 40 -70 years of age • Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body • The progressive degeneration of the motor neurons in ALS eventually leads to their demise • When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost • With voluntary muscle action progressively affected, people may lose the ability to speak, eat, move and breathe

Two Types of ALS • Sporadic • Most common form of the disease in the U. S • Accounts for 90 to 95 percent of all cases. • It may affect anyone, anywhere • Familial ALS (FALS) • Accounts for 5 to 10 percent of all cases in the U. S. • Familial ALS means the disease is inherited • AD, autosomal dominant: 50% chance each offspring will inherit the gene mutation and may develop the disease

Familial ALS (FALS) • In these cases, more than one person in the family has ALS • Sometimes there is a family history of frontotemporal dementia • People with FALS often start showing symptoms at earlier ages than in sporadic ALS, about age 45 • Most affected individuals have mutation(s) in the gene: SUPEROXIDE DISMUTASE 1 or SOD 1, but there are others genes involved in ALS too • Gene mutations can be analyzed using either blood or saliva • Genetic testing for all of the currently known FALS genes can cost from about $1600 to $5000 • Genetic testing for one gene usually costs $500 - $1500. • When the genetic mutation in a family is already known, the cost to test for the familial mutation is usually around $400

Genetic Testing for ALS • Testing is most useful in a person who has been diagnosed with ALS • About 60 -70% of individuals with FALS will have a positive genetic test result (mutation identified) • Those families with FALS where a mutation is not identified may have FALS caused by a gene or genes that have not yet been discovered • Not having an identified genetic mutation does not eliminate a FALS diagnosis and other family members may still be at risk for developing ALS. • If a mutation has been identified, biological family members who don’t have symptoms can be tested to see if they inherited the genetic mutation; this is called predictive testing. Some medical centers may require a neurological exam, psychological assessment and counseling before predictive testing • If a person in the family with ALS has a negative genetic test result (no identified genetic mutation), testing family members without a diagnosis of ALS will not provide more information • If no one in the family with ALS is available for genetic testing, a negative test result in an unaffected person cannot be interpreted.

Genetic Testing for ALS Genetic testing may: • Explain if there is a genetic cause of ALS in the family. • Allow other family members to have testing to see if they carry the genetic mutation. • Allow couples planning on having children to pursue prenatal testing Genetic testing does not: • Currently change medical treatment • Diagnose ALS in people without symptoms • Tell a person without symptoms when they may start showing symptoms or what their progression will be

Epilepsy

Epilepsy • Epilepsy can have both genetic and acquired/environmental causes • Established acquired causes include serious brain trauma, stroke, tumors and problems in the brain as a result of a previous infection • Epilepsy caused by genetic, congenital, or developmental conditions are more common among younger people, while brain tumors and strokes are more likely in older people • Genetics is believed to be involved in the majority of cases, either directly or indirectly • • Some epilepsies are due to a single gene defect (1– 2%) Each of the single gene defects is rare, with more than 200 described Most genes involved affect ion channels either directly or indirectly These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors

Genes and Epilepsy • Twin studies • Identical twins: if one is affected there is a 50– 60% chance that the other will be also • In non-identical twins the risk is 15% • If both twins are affected, most of the time they have the same epileptic syndrome (70– 90%) • Other close relatives of a person with epilepsy have a risk 5 x greater than that of the general population risk of 8/1000 (Epilepsy Foundation) • Most cases of epilepsy are due to the interaction of multiple genes and environmental factors • In 60% of cases the cause is unknown • Genetic testing is more about the medicine prescribed than particular genes for epilepsy

Genes and Immunological Disorders

The Immune System • The immune system is made up of a network of cells, tissues, and organs that work together to protect the body. • To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasites, and distinguish them from the organism's own healthy tissue • We have (1) Innate immune system and (2) Acquired immune system

The Immune System • Innate immune system • Organs such as the lungs, gut, urinary tract system, tonsils • Enzymes that digest bacteria: lysozymes, proteases • Prostaglandins that cause fever • Acquired/adaptive immune system • Our ability to mobilize an immune response against a particular a “foreign” invader to our body • T cells are key to the process • A T cell, or T lymphocyte, is a type of lymphocyte (a subtype of white blood cell) that plays a central role in cellmediated immunity • T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface • They are called T cells because they mature in the thymus from and also in the tonsils • The several subsets of T cells each have a distinct function • The majority of human T cells rearrange their alpha and beta chains on the cell receptor and are termed alpha beta T cells (αβ T cells) • This immune response is controlled by a region in our genome, on chromosome 6, known as the Major Histocompatibility Complex (MHC) • 252 gene loci are present in the 3. 6 Mb of the human MHC, one of the most dense regions in our genome

MHC and HLA • Antigens are present on our cells, vary among individuals of the same species • Antigens are referred to as human leucocyte antigens (HLA) • They are on our white blood cells • Single gene diseases and HLA • Point mutations, deletions and other variants within the MHC are responsible for monogenic diseases showing Mendelian inheritance such as hemochromatosis • Multifactorial diseases • Blood typing established the association between specific HLA antigens and autoimmune diseases such as ankylosing spondylitis, psoriasis and celiac disease as early as the 1970’s

Susceptibility to Disease: HLA Type • Immunological disorders are diseases or conditions caused by a dysfunction of the immune system • Over activity of the system • Attacks the body's own tissues and organs: autoimmune diseases • Autoimmune diseases are associated with genetic variation in the MHC, including the major risk loci for type 1 diabetes, rheumatoid arthritis and multiple sclerosis • Abnormally low activity of the system • Increased susceptibility to infectious disease; can’t fight diseases • Other disease associations include infectious and inflammatory diseases as well as cancer

Autoimmune Disease: Type 1 Diabetes (T 1 D) • T 1 D is a chronic autoimmune disease characterized by T cellmediated destruction of pancreatic islet beta cells, resulting in irreversible insulin deficiency and long-term dysfunction of several organs and tissues • There is no doubt that the major genetic contribution to T 1 D susceptibility arises from the MHC, accounting for approximately 50% of the total genetic contribution to disease • HLA-DQ is the major disease-predisposing locus • Other loci and infection by a virus may bring on disease in people with the HLA-DQ genotype

Autoimmune Disease: Systemic Lupus Erythematosis (SLE) • SLE or lupus, is a multisystem autoimmune disease primarily affecting women of childbearing age • Although no two cases of lupus are alike but common complaints include the following: • • • Swollen, stiff, and painful joints Fever over 100 degrees F Fatigue Rashes on the skin and/or sensitivity to the sun Swelling around the ankles Chest pain with deep breaths Unusual hair loss Pale or purple fingers from cold or stress Mouth ulcers, often painless • In some cases of lupus, several of these symptoms develop at once in what is called a “flare. ”

SLE and HLA • Recent genome-wide association scans and a meta-analysis of linkage screens confirm the MHC as the greatest genetic risk factor in lupus susceptibility • However, the precise contribution attributable to the MHC with respect to overall genetic risk remains to be determined • The most consistent HLA associations with SLE reside with the class II alleles, HLA-DR 3(DRB 1*0301) and HLA-DR 2 (DRB 1*1501) and their respective haplotypes in predominantly white populations • Studies in nonwhite populations have shown inconsistent results • Inherited (and acquired) deficiencies of the early classical complement components, C 2, C 4 A, and C 4 B, encoded within the class III region, are associated with the development of lupus

Autoimmune Disease: Celiac Disease • Celiac disease is a condition in which the immune system is abnormally sensitive to gluten, a protein found in wheat, rye, and barley • The classic symptoms of the condition result from inflammation affecting the gastrointestinal tract. This inflammation damages the villi, which are small, finger-like projections that line the small intestine and provide a greatly increased surface area to absorb nutrients. • In celiac disease, the villi become shortened and eventually flatten out. Intestinal damage causes diarrhea and poor absorption of nutrients, which may lead to weight loss. Abdominal pain, swelling (distention), and food intolerances are common in celiac disease. Inflammation associated with celiac disease may lead to an increased risk of developing certain gastrointestinal cancers such as cancers of the small intestine or esophagus • Inflammation and poor nutrient absorption may lead to problems affecting many other organs and systems of the body in affected individuals such as anemia, vitamin deficiencies, low bone mineral density (osteoporosis), itchy skin rashes, defects in the enamel of the teeth, chronic fatigue, joint pain, poor growth, delayed puberty • Neurological problems have also been associated with celiac disease; these include migraine headaches, depression, attention deficit hyperactivity disorder (ADHD), and recurrent seizures (epilepsy)

Celiac Disease and HLA • Celiac disease is associated with an inappropriate immune response to a segment of the gluten protein called gliadin • This inappropriate activation of the immune system causes inflammation that damages the body's organs and tissues and leads to the signs and symptoms of celiac disease. • Almost all people with celiac disease have specific variants of the HLADQA 1 and HLA-DQB 1 genes, which seem to increase the risk of an inappropriate immune response to gliadin • However, these variants are also found in 30 percent of the general population, and only 3 percent of individuals with the gene variants develop celiac disease • Celiac disease tends to cluster in families. Parents, siblings, or children of people with celiac disease have a 4 -15 % chance of developing the disorder • Appears to be multifactorial inheritance

Genetic Testing for Autoimmune Diseseas • Promethease test for SNPs in genes associated with • Type 1 Diabetes (12 SNPs) • SLE (20+ SNPs) • Celiac disease (seven SNPs) • 23 and. Me • Type 1 Diabetes • Celiac Disease

Infectious Diseases • Infection is one of the leading causes of human mortality and morbidity, with much of the burden falling on children • Infectious diseases are a major selective pressure, and the genes involved in the immune response are the most numerous and diverse in the human genome, indicating the evolutionary advantages of a varied immunological response to a wide range of infectious pathogens • This is most obvious at the HLA loci • For example, individuals in whom all class II HLA alleles are heterozygous are more likely to clear hepatitis B infection, and those with heterozygous class I alleles progress from HIV to an AIDS-defining illness more slowly and have lower mortality • The converse scenario, increased HLA homozygosity, may contribute to the increased susceptibility to infection in genetically isolated populations • There is huge variation in the individual outcomes that follow exposure to potentially life -threatening pathogens, and this differential susceptibility partly shows the functional genetic diversity of the immune response

Infections and Your Immune system • An adequate immune response seems to be related to increased lifespan • Chromosome 6 MHC region • Major Histocompatibility Complex • Region codes Human Leucocyte Antigens (HLA) • The alleles HLA-DR 11 and haplotypes HLA-B 8, DR 3 have a protective effect in infections and are associated with longer life

In Summary. . . • The MHC-HLA is the most polymorphic and gene dense region of the human genome • Genetic variation in the MHC-HLA is associated with more diseases than any other genomic region • These diseases include infectious diseases, autoimmune diseases and cancer • For more information on each of the diseases, and other genetic diseases see the Genetics Home Reference https: //ghr. nlm. nih. gov

The House Health Plan Makes Your Genes a Pre-existing Condition By Adam Rogers, Science writer, Wired, May 4, 2017