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147 Cards in this Set
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what is Nondisjunction?
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-when meiosis fails, nondisjunctioncan occur causing a gamete cell to have an extra or missing chromosome
(+1--> 47 or -1--> 45) -when meiosis fails & doesnt make gametes with 1/2 of DNA from mom and 1/2 of DNA from dad, then we get nondisjunction |
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Aneuploidy
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- if you dont have normal 46 chromosomes, then you have aneuploidy.
e.g. trisomy or monosomic -Downs is the most common chromosome abnormality in babies |
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Aneuploidy
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-if you dont have normal 46 chromosomes then you have aneuploidy e.g. trisomy, monosomy
-Downs is the most common chromosome abnormality in babies -Aneuploidy is increased with maternal age due to nondisjunction |
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Trisomy 21
What is it? |
-Down Syndrome
-there are 3 bodies of chromosome 21 -karyotype of Downs is 47 -21 either XX or XY |
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Physical Signs Of Downs Syndrome
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-Flattened nose
-Single crease in the palm of the hand -Small ears -Small mouth -Upward slanting eyes -Wide, short hands with short fingers -White spots on the colored part of the eye (Brushfield spots) |
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Medical Conditions
with Downs Syndrome |
-Congenital heart defects
-Eye problems -Hearing problems, probably caused by regular ear infections -Hip dislocation -Chronic constipation (Hirschsprung and Celiac disease) -Sleep apnea due to smaller airways -Later tooth development -Hypothyroidism -Dementia |
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Turner Syndrome
(Monosomy X) What is it? |
-Condition that only affects the development of females
-45, X --> most common karyotype of Turners -these females only have one X chromosome |
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Turner Syndrome (Monosomy X)
Common Physical Signs |
-Swollen hands and feet (lymphedema)
-Wide and webbed neck -Absent or incomplete development at puberty, including sparse pubic hair and small breasts -Broad, flat chest -Infertility -Premature ovarian failure -Amenorrhea -Most will have normal intelligence |
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Klinefelter Syndrome
(XXY) WHat is it? |
-Condition that affects the development of males
-47, XXY -It is a trisomy because they have an extra X |
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Klinefelter Syndrome (XXY)
Common Physical Signs |
-Tallness with extra long arms and legs
-Abnormal body proportions -Gynecomastia (breast development) -Lack of facial and body hair -Small testes and penis -Lack of ability to produce sperm -Diminished sex drive, sexual dysfunction |
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Klinefelter Syndrome (XXY)
Medical Conditions |
-Breast cancer
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Triploidy
What is it? |
- when you have a full extra set of chromosomes
-you have 3 copies of each chromosomes (total of 96 chromosomes) -This is not compatible with life -its random |
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Translocations
What is it? |
-When part of chromosomes change locations
-They still have the correct amount of DNA (46), but part of the chromosome is somewhere else |
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Translocation risk to offspring
What do you mean? |
-Means that person can pass on a chromosome that has a mixed chromosome = unbalanced translocation
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Who should be screened for Aneuploidy?
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-American College of Obstetricians and Gynecologists (ACOG) Recommends
that screening tests are offered to all pregnant women to assess their risk of having a baby with a birth defect or genetic disorder. |
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What Can we screen for?
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1) Neural tube defects- incomplete closure of the fetal spine that can result in spina bifida or anencephaly
2) Abdominal wall defects 3) Heart defect 4) Down Syndrome 5) Trisomy 18 /Trisomy 13 -Remember a screening test is not a diagnostic test |
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Important educational points for patients when discussing screening
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-This is only a screening test
-The test is optional -Negative results do not guarantee a healthy baby -Positive results do not necessarily mean a baby will have a problem -Positive results give a reason to consider further testing -Every woman regardless of age has a risk for a fetus with aneuploidy |
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Clinical points to remember about Screening Tests
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-Different screenings can be performed at different times in pregnancy
-Each screen should be discussed and patients should be informed of their choices -Insurance coverage for each screen varies -This should be checked and discussed with the patient before testing -Women with abnormal screens should be offered genetic counseling and perinatal follow-up -Informed consent should always be obtained |
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First Trimester Screening
When is it done? What does it identify? |
-Performed at 10-14 weeks gestation
-Primarily used for identifying a fetus with aneuploidy -Can also identify other birth defects, such as congenital heart defects and diaphragmatic hernia |
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Nuchal Translucency
What is it? |
-An ultrasound can be used to measure the nuchal translucency to determine if there is aneuploidy
-Nuchal translucency is the area behind the neck -If nuchal translucency is increased it may indicate a problem |
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Increased Nuchal Translucency means?
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- > 3mm = 30% risk of aneuploidy
-8.3% of normal fetuses have an increased nuchal translucency -Increased nuchal translucency also associated with CHD, skeletal abnormalities, and diaphragmatic hernia |
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INCREASED NUCHAL TRANSLUCENCY and NORMAL CHROSOMES
what does that mean? |
-Good chance of healthy baby
-20-30% have adverse pregnancy outcome IUFD (intrauterine fetal demise), PTD (Preterm delivery), low birth weight |
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First trimester blood markers
What are they? |
-Another screening tool that has an increased detection rate for aneuplody
- They are: 1) PAPP-A (Pregnany Associated Plasma Protein-A) - & 2) Free B-HCG |
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PAPP-A
(Pregnancy Associated Plasma Protein-A) what is it? |
- Is a first trimester blood markers screening test
-done in 6-11 weeks gestation -Low PAPP-A increases the risk for aneuploidy |
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Free B-HCG
(Beta-subunit of human chorionic gonadotropin) |
-Is a first trimester blood markers screening test
-done in 9-15 weeks gestation -High free B-HCG increases the risk for aneuploidy |
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Using first trimester blood markers alone
What does it offer patient? |
-Increased sensitivity when also combined with maternal age
-If both PAPP-A and Free β-hCG are very low increased risks for trisomy 18, triploidy, and adverse pregnancy outcome |
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NUCHAL TRANSLUCENCY with BLOOD MARKERS IN THE FIRST TRIMESTER
(ultrasound & blood) What does it offer patient? |
-Approximately 90% detection rate for Down syndrome
-Typical window for screening is 10-12 weeks -Can have blood drawn on a different day from ultrasound |
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What are the Benefits of First Trimester Screening?
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-Provides women with a relatively early test to determine whether her pregnancy is at risk for a chromosome disorder or birth defect
-Ultrasound can also be used to date the pregnancy early -Nuchal translucency can assess risks for multiple fetuses |
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What are the limitations of first trimester screening?
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-Not all women enter prenatal care in first trimester
-Ultrasound for nuchal translucency is highly dependent on accuracy by sonographer -Narrow screening window may be missed by many women -Additional cost for first trimester screening -Cannot detect many neural tube defects |
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Second trimester maternal serum screening
When is it done? WHat is it? Types? |
-Performed at 15-20 weeks gestation
-It is a Blood test only (not great if you have multiples) -Two types: Quad vs. Triple screen--> most people do quad screening -Integrated screening available for individuals who underwent first trimester screening -Maternal age is considered -Risk for neural tube defects assessed |
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Benefits of second trimester screening
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-Gives risk assessment for neural tube defects, which is not provided by first trimester screening
-Usually covered by most insurers |
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Limitations of second trimester screening
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-Not as accurate for multiple gestations compared to first trimester screening
-Later gestational age gives less prenatal diagnostic options |
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Integrated Serum Testing
What is it? |
-Combines the blood results from the first and second trimester screening
-Increases detection rate, decreases false positive rate -Helps communities without NT capabilities -Better for patients with low anxiety -Helps patients who cannot afford first trimester ultrasound |
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Prenatal Ultrasounds
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-First trimester ultrasound for NT can also assess absence of nasal bone for increased detection of Down syndrome
-Fetal anatomy scan at 18-20 weeks can identify many major birth defects -Fetal echocardiogram at 20-22 weeks is useful in fetuses at risk due to a genetic disorder, teratogen exposure, or family history of cardiac defect |
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What can you offer a patient with a positive screen?
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- So patient can know more definitively, you can offer them prenatal diagnosis via:
1) First trimester – CVS 2) Second trimester – amniocentesis 3) Fetal anatomy scan & echocardiogram |
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positive screen?
First trimester – CVS |
-done 10-12 weeks gestation
-higher miscarriage risk than amniocentesis -Performed through cervix or abdomen |
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positive screen?
Second trimester – amniocentesis |
- done in 15-20 weeks gestation
-Performed through the abdomen -Also provides additional information regarding NTD -Done for maturity alone, later in pregnancy |
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Chorionic Villus Sampling
WHat is it? |
-First trimester prenatal diagnostic testing
-they are taking placental tissue and measuring chromosomes |
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Amniocentesis
What is it? |
-Its a second trimester prenatal diagnostic testing
-they are testing the amniotic fluid |
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Cordocentesis/ PUBS
What is it? |
-Percutaneous Umbilical Blood Sampling
-Performed after 18 weeks gestation -Uncommonly used -Can be helpful in certain blood conditions -Risk for miscarriage probably greater than 1% |
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Neural Tube Defects
Tell me about them? |
-The neural tube typically closes by the 28th day after conception
-This is usually before a woman recognizes she is pregnant -Neural tube defects can be open or closed -400 μg of daily folic acid can help reduce the risk for NTDs -Pre-conception counseling is important -Spina bifida is the most common NTD |
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Types of neural tube defects
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1) Spina bifida occulta -- no protrusion in the back--->no bone
2) Meningocele- CSF grows out because of missing part 3) Myelomeningocele-- most severe; nerves of spinal column growing in a sac |
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Risk factors for NTDs (Neural Tube Defects) Are?
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-Genetics, family history
-Folic acid intake, nutrition, and metabolism--> important to help prevent NTDs -Teratogens – maternal diabetes, seizure medications, increased body temperature (pregnant women shouldnt go in hot tubs or hot baths) -Probably a combination of genetic and environmental risk factors in most cases |
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How are neural tube defects detected?
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-Second trimester maternal AFP is often elevated in open NTDs
-Amniotic AFP is typically elevated in open NTDs -Second trimester ultrasound can find many open neural tube defects around 18-20 weeks -Anencephaly (when bones of skull don't form) can often be seen earlier |
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Carrier Testing
WHen is it done? |
-When you know there is a genetic disorder in the family & you are testing to see if you are a carrier
-This usually refers to patients who have a family history of a specific genetic condition -It is helpful if the mutation(s) is/are already known for the affected individual -Not usually offered to the general population -Typically autosomal recessive and x-linked disorders |
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Carrier Screening
What is it? |
1) Population-based screening
--> is a particular genetic carrier tests offered to everyone in the general population 2) Targeted population-based screening --> is a carrier screening limited to particular groups of people determined to be at higher risk for specific genetic disorders -Ethnicity-based carrier screening falls under this |
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Principles of Carrier Screening Are?
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-Follow professional society guidelines
-Appropriate for ethnicity -Family history is considered Informed consent -Always optional, discuss possible outcome if testing not performed -Risks/benefits discussed prior to testing -Carrier risks and natural history discussed -Prior to or early in pregnancy to enable more choices for the patient |
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Cystic Fibrosis (CF)
What is it? |
-Gene: CFTR
-Protein: cystic fibrosis transmembrane conductance regulator -Inheritance: autosomal recessive -Most common mutation ∆F508 -CF is most common in Caucasians, but occurs in all ethnicities |
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Cystic Fibrosis (CF
Expressions |
-Affects the lungs, digestive tract, sweat glands, and male reproductive system
-Varied expression and severity (not every1 with CF has the same presentations) -Respiratory: major cause of morbidity and mortality, resulting in lower airway inflammation and chronic endobronchial infection. -Gastrointestinal: 15-20% of newborns with CF have meconium ileus. Pancreatic insufficiency is found in the majority of individuals with CF, which can lead to malabsorption and nutrient deficiency, as well as chronic pancreatitis. -Reproductive: Male infertility may be the only manifestation of CF for some individuals. -Sweat Glands: increased sweat chloride is observed and can be measured. |
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Fragile X syndrome
what is it? |
-Gene: FMR-1
-Protein: fragile x mental retardation-1 -Inheritance: x-linked (mostly affects males) -Most common form of inherited mental retardation -CGG expansion syndrome--> under 44 CGGrepeats is normal -200+ CGG repeats is a Full mutation |
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Fragile X Syndrome
Physical Signs |
-broad forehead
-large prominent ears -strabismus (cross-eyed) -hyperextensible (super flexible) joints -seizures |
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Fragile X Syndrome
Full Mutation: over 200+ repeats |
-All males with a full mutation are affected, and about 50% of females are affected
-Delayed milestones, developmental/speech delay, intellectual disabilities (IQ 30-50), autism, dysmorphism (disformity), and cardiac malformations) |
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Fragile X Syndrome
Pre-Mutation: 55-200 repeats |
-Will present with Fragile X-associated tremor/ataxia syndrome (FXATS)
-males diagnosed at 50 yo -females stop menses prior to 40 yo |
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Spinal Muscular Atrophy
What is it? |
-Genes: SMN1 & SMN2
-Gene SMN1 is the main disease causing allele. -Inheritance: autosomal recessive S/SX: sit with support only, early respiratory failure, ambulation with loss of this ability as the disease progresses |
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Hemoglobin
What is it? |
-Responsible for transporting oxygen to the lungs and tissues
-Can be four types: 1) Alpha 2) Beta 3) Gamma 4) Delta |
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Normal Adult Hemoglobin
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-Consists primarily of hemoglobin A
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Fetal Hemoglobin
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-At birth:
Will have mostly hemoglobin F -At around 5-6 months: Fetal hemoglobin drops to normal levels of less than 3-5% |
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Hemoglobin A2
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-Constitutes less than 3.5% of hemoglobin in normal individual
-Elevated A2 associated with Beta Thalassemia |
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Sickle Cell Anemia
What is it? |
-Autosomal recessive disorder (SS)
-Will contain: Hemoglobin S (90-100% of which are sickle shaped) -Populations affected: African Americans -Characterized by chronic anemia, episodic joint pain, organ damage, and crescent-shaped red blood cells |
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4 Types of Sickle Cell combinations
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1) AS--> means you have the trait; NOT associated with anemia;however avoid hypoxic situations
2) SS--> most common form in African Americans; most severe form of sickle cell disease; 3) SC--> mild to moderate anemia 4) SBeta--> fewer complications than SS |
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Hemoglobin C Disease
what is it? |
-Autosomal recessive
-Causes hemolytic anemia -Considered to be benign in some cases -Populations affected: African American Hispanic Sicilian -Characterized as having unstable hemoglobin -Forms crystals -Leads to decrease in RBC rigidity and viscosity of the blood -Can get build up within the spleen |
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Beta Thalassemia
What is it? |
-Genetic blood disorder
-Autosomal recessive -Characterized as not being able to make enough hemoglobin -Causes severe anemia -Low levels of oxygen in all parts of the body -less beta thalassemia genes you have the more severe symptoms will be |
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Types of Beta Thalassemia
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1) Beta Thalassemia Trait (Minor)-->
Mild anemia and pallor 2) Beta Thalassemia Homozygous (Major)-->Also known as Cooley’s anemia -Inherited defect in beta chain synthesis -Affects Mediterranean, Asian, and African American -Jaundice, splenomegaly, bone malformations, weakness, growth restriction, shortened lifespan, & severe anemia |
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Alpha Thalassemia
what is it? |
-Caused by genetic disorders of alpha genes
-Decrease in alpha chain synthesis -Results in severe anemia -Commonly found in people of Asian origin -Four classifications |
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Types of Alpha Thalassemia
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1) Single gene deletion--> aka Silent Carrier--> clinically & hematologically normal
2) Deletion of 2 alpha genes--> mild anemia w/ small red cells; no evidence of iron deficiency; 3) Deletion of 3 alpha genes--> moderately severe anemia resembling Cooley's anemia 4) Deletion of 4 alpha genes--> most severe; fetal hydrops syndrome; severe hemolytic anemia;heart failure, stillborn births;high rate of toxemia in pregnancy & postpartum bleeding |
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Conditions recommended by ACOG for carrier screening among Eastern European Jewish populations
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1) Tay-Sachs disease
2) Cystic Fibrosis 3) Canavan disease 4) Familial Dysautonomia |
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Tay-Sachs disease
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Autosomal recessive disorder
-Disease of the nervous system -Body lacks hexosaminidase A -this Protein that breaks down gangliosides -Without this protein, build up in nerve cells -Infantile form most common -Symptoms appear when child is 3-6 months old -Children usually die by age 4 or 5 |
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Tay Sachs Disease Symptoms
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-Deafness
-Decreased eye contact, blindness(primary sx) -Hypotonia -Delayed mental and social skills -Dementia -Paralysis (by 4-5 yo) |
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Canavan disease
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-Autosomal recessive disorder
-Condition that affects the break down of aspartic acid -Leads to buildup of N-acetylaspartic acid in the brain -Causes white matter of brain to break down -Symptoms begin 1st year of life -Death usually occurs before 18 mo. |
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Symptoms of Canavan Disease
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-Abnormal posture with arms and legs
-Feeding problems -Macrocephaly (increased head size) -Lack of head control -Reflux with vomiting -Seizures -Severe mental retardation |
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Familial Dysautonomia
What is it? |
-Autosomal recessive disorder
-Disorder of the autonomic and sensory nervous systems -Affects the development and survival of sensory, sympathetic and some parasympathetic -Incomplete development of sensory and autonomic neurons |
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Familial Dysautonomia
Symptoms |
-Poor growth
-Seizures -Inability to produce tears -Inappropriate perception of heat, pain, taste -Poor coordination -Does NOT affect intelligence -Severe scoliosis |
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Extended carrier screening panel recommended by ACOG for persons of Eastern European Jewish descent
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1). Niemann-Pick (Type A)
2). Fanconi Anemia (Group C) 3). Bloom Syndrome 4). Gaucher Disease 5). Mucolipidosis Type IV |
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Niemann-Pick (Type A) Disease
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-Autosomal recessive disorder
-Enzyme: Acid sphingomyelinase -Breaks down lipid called sphingomyelin -Deficiency in enzyme causes accumulation of sphingomyelin and cholesterol in lysosomes -Causes fatty deposits to collect in the cells of the spleen, liver, and brain -Usually fatal by by 4 years of age |
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Niemann-Pick (Type A) Disease
Symptoms |
-Type A usually begins in the first few months of life
-Progressive -Abdominal (belly area) swelling within 3 - 6 months -Cherry red spot in the eye -Feeding difficulties -Loss of early motor skills |
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Fanconi Anemia (Group C)
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-Mutation in gene: FANCC
-DNA damage is not repaired efficiently and stalls DNA replication -Results in either abnormal cell death or uncontrolled cell growth -Affects cells that divide quickly, such as bone marrow cells and fetus cells (aplastic anemia -Results in the decrease in blood cells |
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Fanconi Anemia (Group C)
prognosis |
-Prone to infection
-Bleeding problems -Greater risk to developing cancers -Leukemia -Solid tumors -Bone marrow failure -Anemia -Lifespan is unpredictable |
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Bloom Syndrome
What is it? |
-Mutation in gene: BLM whose function is to Maintain DNA stability during the copying (very rare)
-Indicator of chromosome instability -Associated with gaps and breaks in the genetic material -Cause these health problems: Cancer Cells divide uncontrollably -Slow Growth Increase in cell death |
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Bloom Syndrome
Symptoms |
-Short stature
-Sensitive skin (especially to the sun) -Increased risk of cancer at young age (skin cancer) -Low birth weight and length -High-pitched voice Distinctive facial features -COPD -Absent (men) or reduced (women) fertility |
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Gaucher Disease
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-Mutation in gene: GBA
-Lipid storage disease -Inability to metabolize essential compounds -Causes lipids composed of ceramide and glucose to accumulate -Enlarging both the liver and the spleen (Ginormous abdominal area) |
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Gaucher Disease Symptoms
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Variable expressivity (bc of 4 types)
-Brittle bones -Restricted movement in joints -Brown spots on the skin -Raised, yellowish areas near cornea |
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Mucolipidosis Type IV
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Mutation in gene: MCOLN1
-Lysosomal storage disorder -Lack of functional MCOLN1 impairs transport of lipids and proteins -Causing substances to build up -Characterized by delayed development and progressive vision loss |
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Mucolipidosis Type IV
Symptoms |
-Intellectual disability
-Limited or absent speech -Difficulty chewing and swallowing -Hypotonia -Spasticity -Difficulty controlling hand movements -Psychomotor delay |
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what is a Lysosome?
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-Lysosomes are Enzyme containing vesicles (organelles)
-Primary purpose: intracellular metabolism & digestion of certain products Found in a variety of cells (example: WBC - Lysosome is responsible for killing & digesting bacteria) |
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What are lysosomal storage diseases?
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-Term used to describe a group of approximately 50 genetic diseases
-Gene Defect causes abnormal enzyme activity (body not breaking down products appropriately): 1) Decreased or Absent enzyme activity (absent or decreased will determine severity of symptoms) OR 2) Defect in a 3) Results in -Accumulation of undigested (or partially digested) substrates within the Lysosome |
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Pathophysiology of LSDs
(Lysosomal Storage Diseases) |
- Is the Accumulation of the substrate causes cell dysfunction & death
-Pattern of degeneration is cell specific: -Little cell turnover in the CNS (equals Greater damage to the CNS/brain) -Usually related to amount of residual enzyme activity (Greater residual enzyme activity = less cell damage) |
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Cause & Effects f LSDs
(Lysosomal Storage Diseases) |
-Abnormal disposition & storage of a particular substance can result in:
1) Cellular dysfunction & clinical abnormalities 2) Systemic Manifestations such as: -Muscle weakness -Bone Disease -Organomegaly -Connective tissue pathology -Ocular abnormalities 3) Effects on the CNS -Progressive neurological deterioration |
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Genetics of LSDs (Lysosomal Storage Diseases)
Are LSDs Autosomal Recessive? |
- Yes, Majority inherited as Autosomal Recessive
a) May be X-Linked Recessive b) X-Linked Dominant -Significant phenotypic differences between family members with same mutations reported |
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Clinical Presentation of LSDs (Lysosomal Storage Diseases)
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-They Vary in Severity, Expression & Age of Onset
-ie: Infantile, Juvenile, Adult onset Gaucher, Pompe -May be misdiagnosed |
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Treatments for LSDs (Lysosomal Storage Diseases)
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1) Enzyme Replacement Therapy (ERT)--> giving back enzyme that you're missing
-Administered IV 3 x per week up to Once per month Expensive (can be over ½ million $ per yr.) -Generally Safe, Effective (May develop antibody reactions similar to blood products) -Does not cross the Blood–Brain barrier ( So, Not effective if LSD effects CNS/brain--> one of the shortfalls of ERT treatment) -Treatment available for 6 Diseases |
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Diseases Treated by ERT (Enzyme Replacement Therapy)
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Gaucher Disease (I & 3)
Pompe Disease |
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Other Treatment Options for LSD (Lysosomal Storage Diseases)
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1) Substrate Reduction Therapy :
-FDA approved for Gaucher Disease -Reduces the formation of offending protein (Oral (3 x day) -GI Side effects similar to lactose intolerance-->Usually resolves with diet management & Graduated dosing -can cause Peripheral Neuropathy -May cause --> Infertility in men, childbearing age women have to go on birth control Fetal malformations / fetal death |
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What is Gaucher Disease?
Is it autosomal recessive? which gene is mutated? |
- Gaucher Caused by a mutation in the GBA gene
-It is a Lysosomal Storage Disease (LSD) -Higher in Ashkenazi Jewish Population -it is Autosomal Recessive -Prenatal & Carrier testing available Dor Yeshorim: Must request premarital testing |
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What are the 3 Clinical Types of Gaucher Disease?
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1) Type I
-Mildest with large clinical variability -Non-neuronopathic -doesnt have CNS disbability 2) Type II -Severe / Lethal -Neuronopathic -infant onset; HAS CNS disability problems present right after birth -you also see enlarged liver & spleen with Type II 3) Type III -Intermediate |
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What is Gaucher Disease Type I ?
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-Most Common type
-Most common Genetic Disorder in Ashkenazi Jews -Chronic -Age of onset variable: Infancy to Adults -Gaucher cells infiltrate the 1) Liver (Enlarged – Hepatomegaly) 2) Spleen (Enlarged - Splenomegaly) 3) Bones (Fractures, Pain, Necrosis)--> can have bone infarct so severe that it causes bone pain b/c blood cant get to that part of the bone 4)Blood (Anemia, Thrombocytopenia, Infections)--> come into ER and first sign is nosebleed 5)Cardiac & Lung (less often or later) |
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What is Gaucher Disease Type II ?
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It is Neuronopathic
-Acute -Onset: Infancy -Neurological (abnormal cells in CNS/brain) - presents w/ hypertonia, retroflexion of the head -Abnormal movements of the eyes -Hepatomegaly, Splenomegaly -No effective treatment: Death by 1-3 years |
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What is Gaucher Disease Type III ?
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-It has Subacute / Slower onset of symptoms
-Appears in infancy -Horizontal gaze palsy -Neurological problems -Hepatomegaly -Splenomegaly -Cardiac (valvular disease) -Pulmonary -Lymphadenopathy |
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Nursing Considerations for Gaucher Disease
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- Evaluations
1) Labs ie: -Diagnosis: Enzyme Level & Mutation Analysis -CBC / Platelets -Gaucher specific markers: Chitriosidase , ACE, TRAP 2) MRIs: -Abdomen & Spleen size -Bone Involvement 3) X-rays: -Spine / Femurs--> can have curvature of the spine -DEXA : Bone Density 4) Long term Port Placement for Children (via IV) |
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What is Pompe Disease?
(aka Acid Maltase Deficiency or Glycogen Storage Disease Type II) |
-Pompe Disease is the Decreased or absent production of the enzyme acid alpha-glucosidase ( aka acid maltase)
- It is also the Accumulation of glycogen in organs & tissues -Inheritance: Autosomal Recessive -It is a Lysosomal Storage Disease (LSD) -Higher incidence in African & Chinese Ancestry -Caused by a mutation in the GAA gene Diagnosed by: Enzyme Assay & Mutation Analysis |
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3 Types of Pompe Disease are?
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Three types:
1) Classic Infantile Onset 2) Non-Classic Infantile Onset (Juvenile) 3) Late Onset (Adult) Diagnosed by Enzyme & Mutation Analysis |
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Symptoms of Pompe
(Classic – Infantile Onset) |
-Most Severe
-Onset of symptoms in the first 6 months of life -Rapidly progressive -Macroglossia--> big tongue/usually sticking out--> cardinal sign -Cardiomegaly -Motor weakness, Hypotonia (muscle weakness), Head Lag -usually can't talk b/c jaw muscles are so weak -Respiratory insufficiency (often intubated/trached) -Feeding difficulties (G-tube) -Usually have no intellectual impairment -Death prior to age 2 if Untreated |
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Symptoms of Popme
(Adult / Juvenile Onset Acid Maltase Deficiency) |
-Onset of symptoms in childhood or adulthood
-Slowly progressive, chronic -Progressive proximal muscle weakness (Manifestations may be limited to skeletal muscle) -Respiratory Dysfunction-->most of them have this (Difference between lying & sitting--> may not be able to breathe if laying down) -The Major difference between adult onset & infantile is the ABSENCE of cardiac involvement in the Adult onset version** |
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Treatment / Prognosis for Pompe Disease
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1)Enzyme Replacement Therapy for Life
-Usually given IV every 2 weeks -No oral treatment FDA approved at this time -Earlier the treatment is started the better the outcome -Treatment is effective in improving, or reducing progression, of cardiomegaly, respiratory involvement, muscle weakness in most individuals -Increased Protein Diet (low carbs, low fat, high protein) |
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Nursing Considerations (Labs & Studies)vfor Pompe Disease
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1) Lab tests
CPK / CMP / EGFR 2) Studies -CXR -Cardiac Evaluation with ECHO / EKG -Pulmonary Evaluation: PFTs / Sleep Study -EMG -Physical Therapy -Nutrition Evaluation |
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What is Phenylketonuria (PKU) ???
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-Enzyme (phenylalanine hydroxylase - PAH) in liver is deficient (majority of cases)
- This deficiency Leads to elevated levels of phenylalanine (amino acid) in the blood & other tissues -If left Untreated may cause: Developmental delay Mental retardation (SEVERE) Autism Microcephaly Seizures Eczema |
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Health Concerns for PKU
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1) Osteopenia
May be related to non-compliance with diet 2) Vitamin B 12 deficiency -Found in natural animal protein--> but they can't eat regular animal protein b/c their bodies can't breakdown protein -Available in special medical formulas -Deficiency may be related to non-compliance with diet / treatment 3) Psychological Issues ie: depression 4) They are put on a phenylalanine restricted diet |
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Genetics of PKU?
Is it autosomal recessive? |
- It's Caused by a mutation in the PAH gene
-Chromosome 12 -Autosomal Recessive -Prenatal testing is available for known mutations |
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3 types of PKU are?
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1) Classical PKU
Complete (or near complete) deficiency of PAH enzyme activity 2) Non Classical (Non-PKU Hyperphe) Based on PHE tolerance Moderate Mild Mild Hyperphenylalaninemia 3) Variant |
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treatments for PKU are?
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1) Diet for Life
-Phenylalanine (PHE) restricted diet -Elemental amino acids medical formula -Modified low protein products -Limited natural foods -Essential amino acids necessary for brain & body growth 2) Blood Levels must be monitored weekly during first year of life -Gradual increase in testing interval as child grows -Monitored frequently during periods of illness or body stress (adolescence) --> b/c levels can be high during these times |
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what is Maternal PKU ?
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-Effects on Fetus are based on mother’s PKU, not because the infant has the disorder
-Phenylalanine crosses the placenta -More concentrated in fetal blood -Dose responsive (higher the level, greater the effects) -Microcephaly -Mental retardation -Low birth weight -Congenital heart disease -Facial dysmorphism -We monitor pregnant moms --> ideally before conception--> we monitor their diets b/c effects of diets can't be reversed |
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Tell me about DNA
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-Our DNA is encoded into RNA
-RNA is sliced up and put together as MRNA, before it goes out to make proteins |
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whats a codon?
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- A codon is made of 3 base pairs that we get to put together to put proteins
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what are mutations?
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-Mutations are Alterations in the genetic code from the normal base pair sequence
-3 Types: 1) Point (silent, mis-sense, non-sense) 2) Insertions/Deletions (in-frame, frame-shift) 3) Splice Site 4) Chromosomal |
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What is Polymorphism?
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-Polymorphism is a mutation
-not all mutations are bad ie: polymorphism - Polymorphisms are Normal genetic variants that do not harm the protein function -they make each of us different from everyon1 else ie: blue eyes, blonde hair |
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What is a pathogenic mutation?
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Pathogenic Mutations
- they are Disease causing mutations that alter protein structure and/or function -NONSENSE MUTATIONS are the most commonly seen pathogenic mutation -they are nonfunctional or missing a protein |
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4 types of Point Mutations are?
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1) Normal
2) Silent-no amino acid change 3) Missense--amino acid change 4) Nonsense- most common type of pathogenic mutation -makes protein stop short aka truncated mutation -if protein is not transcribed to its full length, it wont be able to to do what its supposed to do |
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what is a point mutation?
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- Is a change in a single base pair
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What is a frameshift point mutation?
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frameshift point mutations jumble everything up
-there are diff types --they alter amino protein and genetic pattern -frameshift (mutation is NOT of multiple 3 bases) more likely to be pathogenic than inframe mutation (which is a mutation of multiple 3 bases) |
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4 types of chromosomal mutations are?
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-Translocations
-Large duplications/deletions -Full gene duplications/deletions -Chromosome inversions |
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What is a Germline mutation?
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- they are Hereditary (passed on from generation to generation)
-Present in egg or sperm--> they occur in our germ cells which are our egg & sperm -Syndromic--every single cell in our body has the mutation |
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what is a SOMATIC mutation ?
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1) Not inherited (not in our egg/sperm)
2) Acquired--> something acquired over time that happens in a SINGLE cell -can be random or spontaneous 3)Non-syndromic--only 1 cell in the body has the mutation & then that cell gets repeated mutations & has potential to turn cancerous |
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what happens if things go wrong in cell cycle?
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When things go wrong in cell cycle, it can have cancer cells that develop
-ie: turning a gene on or off or repairing a gene thats broken |
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Tell me about cancer cell growth?
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-it has no cell death, it keeps growing
-it acquires a mutation & keeps on dividing & has the potential to become cancerous -Remember, 1 mutation is not cancer -Cancer is a multi-step process |
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What is Tumorigenesis ?
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The multi-step process by which normal cells transform into tumor cells
-not all tumors are cancer |
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What is a Benign tumor?
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-Non-cancerous growths
-Do not spread to other parts of the body -When removed, they usually don’t come back |
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What is a Malignant tumor?
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-Cancerous growths
-Invade nearby tissues -Metastasis = spread to other parts of the body |
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Cancer
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-All cancer arises from mutations
-Tumorigenesis is a multi-step process -5-10% of cancer is hereditary |
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Germline testing provides:
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Germline testing provides:
-Diagnosis of genetic conditions -Prediction for identifying individuals at risk -Potential gene targeted therapies -Prognostics |
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Features of Hereditary Cancer
PATIENT SIDE--> if patient has this , might be a hereditary cancer |
1) Multiple primary tumors
2)Bilateral primary tumors 3) Younger-than-usual age at diagnosis 4) Tumors occurring in the sex not usually affected (e.g., breast cancer in men) 5) Non-random associations ie: breast Ca and ovarian Ca |
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2 main forms of Cancer development are:
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1) Oncogenes
2) Tumor Suppressor Genes |
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What is an Oncogene ?
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1) They Accelerates cell division--> they make more cells
2)Cells are stuck in “on” mode--> they push cell cycle forward 3) Gain of function--> w/ oncogenes, cells gain abilities that can lead to cancer |
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What is a tumor suppressor gene?
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1) They are: DNA damage response genes
2)They are supposed to Slows/stops cell growth (if something wrong is going on) 3) Loss of function--> when tumor suppressor genes lose that ability to stop/slow cell growth, that is what leads to cancer -tumor suppressor genes themselves are NOT cancer genes, they are actually protective. Its only when these genes are mutated or lose their ability is when they have the potential to be cancerous |
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Example of disease process for Oncogene
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1) Chronic Myelogenous Leukemia (CML)
-its a Non-hereditary, but genetic form of cancer -aka The Philadelphia Chromosome -there is a Fusion of proteins resulting in uncontrolled blood cell production |
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what is the Two-Hit Hypothesis ?
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-its when there is a first hit inn the germline of the child--> but it DOESNT cause anything b/c the the first mutation is inherited
-When there is a second hit (tumor), this second mutation is acquire--> & it can lead to a tumor--> it can be random or spontaneous -two-hit thypothesis correlates with patient side features of hereditary cancer |
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Example of a disease process for Two-Hit Hypothesis ?
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1) Retinoblastoma
-RB1 gene -Mutations result in loss of cell cycle regulation -Younger age and bilaterality increase risk for inherited form -Positive family history see in 10% of cases (usually not inherited) |
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What is DNA DAMAGE REPAIR?
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-DNA damage is a natural part of human existence
-Luckily our DNA knows how to detect these mutations and repair itself!!!! |
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2 TYPES of DNA Damage repair are ?
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1) DNA nucleotide excision repair
ie: Xeroderma pigmentosa 2) DNA mismatch repair ie: Lynch syndrome |
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What happens w/ nucleotide excision repair?
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-Its a type of DNA damage repair
1) Damage occurs 2) Damage is recognized 3) DNA is opened to expose single strands – normal and damaged 4) Enzymes cut off damaged DNA 5) Damaged DNA is removed 6) DNA re-synthesized with normal genetic code |
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Example of a disease process where nucleotide excision repair doesnt occur ?
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1) Xeroderma pigmentosum
-it is autosomal recessive (very rare disease) - Characterized by an extreme sensitivity to ultraviolet (UV) rays (Deficient repair of DNA damaged by UV radiation)--> u get multiple malignant skin cancers |
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Clinical Symptoms of Xeroderma pigmentosum are ?
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-Clinical symptoms characterized in stages
-Stage I: Erythema, scaling, and freckle-like areas of increased pigmentation (occurs at 6 months) -Stage II: Poikiloderma - mottled hyperpigmentation, scaly papules and nodules, ulcers and crusts -Stage III: Appearance of numerous malignancies including: squamous cell carcinomas, malignant melanoma, basal cell carcinoma, and fibrosarcoma (Occurs at age 4-5) -normally your skin will correct these clinical symptoms |
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Tell me about DNA Damage Detection
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-Our DNA not only needs to fix a problem, but it also needs to be able to detect a problem
-2 main genes that do that are: 1) ATM--> breaksdown/splits both genes 2) ATR--> it comes to the rescue of single DNA strand breaks |
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Example of a disease process where DNA DAMAGE DETECTION doesnt work ?
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1) Ataxia telangiectasia
-ATM gene--> not working from a young age -it is Autosomal recessive Progressive cerebellar dysfunction between ages 1-4 Ocular and facial telangiectasias Immunodeficiency Cancer: radiation sensitivity because DNA can not be fixed Leukemias and lymphomas in childhood Other cancers present later if the child lives long enough |
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Symptoms of Ataxia telangiectasia
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-Progressive cerebellar dysfunction between ages 1-4
-Ocular and facial telangiectasias -Immunodeficiency -Cancer: radiation sensitivity because DNA can not be fixed (Leukemias and lymphomas in childhood) (Other cancers present later if the child lives long enough) -they are extra sensitive to radiation |
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Example of a disease process that doesnt have DNA DAMAGE RESPONSE?
DNA DAMAGE RESPONSE = YOU FOUND A DAMAGE & NOW YOUR RESPONSE IS TO SLOW GROWTH, REPAIR DNA, OR CELL DEATH (APOPTOSIS) |
-Li Fraumeni Syndrome
-TP53 gene tells cells to die--> the lack of this means cells can live forever & acquire more mutations -they develop cancers over & over again -sensitive to radiation |
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What type of tumor environment allows cancer to escape cell death ?
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- To succeed, cancer cells need to escape DNA repair & cell death, and have the cooperation of their environment
Environmental disruptors include: Inflammation Wounding Infection Hormones Weak immune system |
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What is Angiogenesis ?
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- the Growth of blood supply for tumor
-Necessary for tumor to grow larger |
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Steps of Tumorigenesis Are ?
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1) Cells lose their normal abilities
-de-differentiation--> no longer a skin cell now a tumor cell (gaining 2) Cells gain the ability to divide uncontrollably - proliferation 3) Cells have unregulated cell cycle - bypass check points (ie: oncogenes or tumor suppressor cells) 4) Cells cannot fix DNA damage - avoid damage response and repairs 5) Cells avoid death - no apoptosis (TP53 gene) 6) Cells stimulate growth factors - signal for angiogenesis (this is when u become a malignant cell) 7) Cells spread to surrounding tissues and other organs - metastasis |
