Exam 1 - Lecture 2 Flashcards
What are the symptoms of alzheimer’s disease?
Early: Memory problems
Middle: Troublesome behaviors
Late: Activities of daily living suffer
What are examples of multifactorial disease?
- Alzheimer disease
- Coronary Artery disease
- Diabetes Type I (childhood onset)
- Diabetes type II (adult onset)
- Hirschprung disease (here factors are all genes)
- Neural tube defects
- Schizophrenia
- Obesity
What are the risk of having alzheimer’s?
- If 1st degree relative has Alzheimer’s - 30% lifetime risk (3-4 times increase)
- Twin concordance rates: 30-80% for monozygotic; 10-40% for dizygotic
Heritability (H) estimates (0.44 to 0.8)
What is the rate of inheriting Alzheimer’s as a monogenic disease?
1% unless autosomal domain
APP mutations (5%) (Most common = Val 717 Ile)
Presenilin-1 mutations (70%)
Presenilin-2 mutations (<5%)
What is the rate of inheriting Alzheimer’s as a multifactorial disease?
99%
What is Amyloid Precursor Protein (APP)?
Amyloid precursor protein (APP) is a membrane protein that sits in the membrane and extends outward.
What do secretases do?
enzyme that cuts B-amyloid peptides into fragments
What are b-amyloid fragments?
β-amyloid fragments are “sticky”, forming the plaques seen in the AD brain.
What is the function of Presenilin?
The presenilin proteins are part of the γ-secretase complex, which snips fragments off amyloid precursor protein (APP), releasing β-amyloid peptide into the extracellular space where it form plaques.
What is presenilin?
subcomponents of gamma-secretase mutations in PSEN1/2 leads to a gain of toxic function
Describe Presenilin mutation
Biochemically = partial loss of the γ-secretase complex function, which affects several downstream signaling pathways.
What are the other genes involved in multifactorial alzheimer’s?
APO E4 (encoded by a gene on chromosome 19), and a major risk factor for multifactorial Alzheimer’s
What are the environmental factors in alzheimer’s?
Serious head injury, High blood pressure, heart disease, stroke, diabetes and high cholesterol, Being engaged with active learning, Smoking
What are the variants of APO?
APOε2 decreases risk for AD
APO E4 binds to Aß in cerebrospinal fluid, found in plaques in AD brains, and increase risk for AD
What is punch-drunk syndrome?
a condition seen in boxers, often years after their retirement, and presumably caused by repeated cerebral injury
What is evidence for gene-environment interaction in alzheimer’s?
Risk for AD after severe head injury with loss of consciousness is much greater in individuals with one or more APOE4 alleles
Which genotypes are more at risk for AD?
E2/3, and 3/4
What is coronary artery disease?
CAD is a family of diseases that include hypertension, atherosclerosis, coronary heart disease, and stroke
Why is CAD worse in females?
because it is more common in males, so if a female has it, then its is worse
What is the concordance of CVD in twins?
Concordance : 40-65% (monozygous); 15-30% (dizygous)
What enzyme plays a role in CAD?
ACE - CAUSES VASOCONSTRICTION, INCREASE ALDOSTERONE AND ADH SECRETION, INCREASE THIRST
What does ACE inhibitor do?
ACE inhibitors block the Angiotensin Converting
Enzyme (ACE).
What hormones increase plasma glucose?
glucagon, epinephrine, cortisol, and growth hormone
What hormones decrease blood glucose?
insulin
Why is high plasma glucose bad?
- Activation of the protein kinase Cβ
- Glycation
- Oxidative stress
- Depletion of NAD+ (metabolic pseudohypoxia)
- Vascular dysfunction in the kidneys
What is the result of hyperglycemia induced activation?
Diabetic kidney leaks protein, and High blood pressure
What quantified AGE elimination by the kidneys ?
HbA1c; Every 1% ↓ HbA1C results in 30% decrease in Microvascular Complications
How are AGE formed?
Non-enzymatic reaction of proteins (and DNA) with glucose and and formation of adducts –> advanced glycation endproducts (AGEs).
What is IDDM?
Diabetes Type 1 (IDDM)
Insulin-dependent diabetes mellitus (IDDM)
Juvenile-onset diabetes
What is NIDDM?
Diabetes Type 2 (NIDDM)
Non-insulin-dependent diabetes mellitus (NIDDM)
Adult-onset diabetes
What is destructed in type 1 diabetes - autoimmune?
Selective destruction of β-cells by T cells and Several circulating antibodies against β-cells
What is the prevalence of hypoinsulinemia?
see in 10% of diabetic cases, and 1/200 people
What is the 1DDM1 Locus?
HLA Region - HLA DR3/4-DQ2/8 genotype
What is the 1DDM2 Locus?
in insulin gene INS
What allele influences INS?
14-bp VNTR repeat influencing transcription of INS
What does VNTR do?
Allele reduces expression of insulin in fetal thymus, reducing immunotolerance to insulin and pancreatic Island cell later in life
What are the rates of IDDM1 and INS?
50% for IDDM1 and 10% for INS
How do you calculate the heritability of diabetes?
a = risk of siblings/population prevalence
What are the heritability for diabetes 1 and 2?
1 = 15% 2 = 3-4%
What is hyperinsulinemia?
insulin resistance
How is type 2 diabetes treated?
oral hypoglycemics
What is the rate of concordance in type 2 diabetes for twins?
90% (monozygous); 30-40% (dizygous)
What is MODY-Diabetes?
MODY (maturity-onset diabetes of the young)
Type I-like diabetes that is inherited as autosomal dominant disease (monogenic)
What are the various mutation in MODY?
MODY1 (HNF4)
MODY2 (glucokinase)
MODY3 (HNF1)
MODY4 (IDX1 islet-duodenum homeobox)
Whats causes Hirschsprung Disease?
the Absence of ganglion cells in the parts of the colon and rectum
What are the effects of short-segment HSCR disease?
affects the rectum and small portion of the colon 60−85% of cases
What are the effects of long-segment HSCR disease?
affects a longer portion of the intestine; 15−25% of cases.
What are the syndromic and nonsyndromic fates of HSCR?
70% - nonsyndromic forms (isolated)
30% - syndromes (other problems)
Which segment of Hirschsprung Disease is more severe?
long-segment is more severe than short segment
3-4% and up to 17% in siblings (4:1 male to female)
What type of disease is Hirschsprung disease?
oligogenic
what are the 3 types of neural tube defects?
anencephaly, spina bifida, encephalocele, meningocele, myelomeningocele
What are the genetic risk of neural tube defects?
Risk for first degree relatives - 4/100
Risk for second degree relatives - 1/100
Risk in population (before prevention) – 3/1000
How is hyperhomocysteinemia caused?
caused by a deficiency of B vitamins and folate in diets, hypothyroidism, MTHFR C677T
What are the risk associated with elevated homocysteine levels?
Coronary artery disease (atherosclerosis): Heart attack, and Stroke
Peripheral arterial disease: Venous thrombosis, Deep vein thrombosis, Pulmonary embolism
Dementia
Having a child with a neural tube defect (ie, spina bifida)
What are some symptoms of schizophrenia?
delusions hallucinations incoherence catatonic or hyperactive behavior flat affect
What is the heritability for schizophrenia?
0.8 and 0.85
what illnesses show strong correlation with schizophrenia?
strong positive correlation between schizophrenia, bipolar disorder, and autism, suggesting that they are caused by a common group of genes
Hep B and minogoccus overlap with what neurological diseases?
migraines (strong correlation with autism), autism, and schizophrenia
What is Direct-to-Consumer Genetic Testing?
Any genetic test accessible directly to the consumer without having to go through a healthcare professional.
A variety of DTC tests ranges from testing for mutations linked to cystic fibrosis to hypertension predisposition.
The lack of governmental regulation leads to a risk of potential misinterpretation of genetic information.
What does a loss of function of presenilin causes?
The loss of function of presenilin causes incomplete digestion of the amyloid β-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease.
Dementia and APO4
Dementia risks are selectively increase in APOE4 carriers
What alleles are associated with CAD?
ACE DD, ID, II alleles: DD genotype is associated with CAD
how is hypo hyperinsulinemia treated?
hyper - oral hypoglycemics
hypo - insulin injections
What is the Genetic Information Nondiscrimination Act?
Prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future
Bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions
What is the evident for gene-gene interactions?
Patients with PSEN1 mutation and E4 allele develop disease earlier than those with PSEN1 mutation and E3/E2 alleles
breast cancer and mental illness
Genes that make women more vulnerable to breast cancer appear to be somewhat protected against bipolar disorder and schizophrenia
What are the symptoms of punch drunk syndrome?
weakness in the lower limbs, unsteadiness of gait, slowness of muscular movements, tremors of hands, dysarthria, and slow thinking.
What is insulin resistance?
the normal amount of insulin secreted by the pancreas is not enough stimulus for the cells to make them uptake the glucose (cells are insulin resistant)
What is the hertability for neural tube defects?
Heritability = 0.6
