Genetic and Congenital Disorders Flashcards
1
Q
causes of birth defects
A
- genetic factors
- environmental factors
- intrauterine factors (rare)
2
Q
genetic factors causing birth defects
A
-permanent genomic change
-Single-gene defect
chromosomal aberrations
-multi-factorial inheritance –> we think most human dz is a result of this
-many congenital disorders are fatal to the embryo or not compatible with life so baby dies after birth
3
Q
environmental factors causing birth defects
A
- fetal development issues
- ZIKA is an example!
- Gestational diabetes and obesity
- Maternal disease, infections, or drugs during pregnancy
- Drugs –> fetal alcohol syndrome, babies born addicted to heroin
4
Q
intrauterine factors causing birth defects
A
-fetal crowding, positioning, or entanglement of fetal parts with the amnion
5
Q
single-gene disorders
A
-follow Mendelian genetics
-Autosomal Recessive
Autosomal Dominant - >50% of all single gene dz
-X-Linked Dominant
-X-Linked Recessive – Most sex-linked d/o
-Y-Linked Inheritance – spermatogenesis/not transmitted
-Mitochondrial Inheritance
6
Q
autosomal recessive vs. dominant - onset
A
- R: early uniform onset (infancy/childhood)
- D: variable onset (may be delayed into adulthood - HD)
7
Q
autosomal recessive vs. dominant - pattern
A
- R: requires 2 mutant alleles, may “skip” generations
- D: usually inherited from affected parent, sporadic cases possible
8
Q
autosomal recessive vs. dominant - penetrance
A
- R: complete penetrance
- D: incomplete penetrance with variable expression
9
Q
autosomal recessive vs. dominant - mutation
A
- R: usually an enzyme protein
- D: usually a structural protein or receptor
10
Q
autosomal recessive vs. dominant - requires
A
- R: mutation of both alleles
- D: mutation of one allele
11
Q
Marfan’s syndrome
A
-Fibrillin I defect
-EC matrix component for elastin deposition
-Sporadic cases possible
-Bilateral lens dislocation
-Often associated with aortic dissection
-A connective tissue disorder
-Mutation of the fibrillin gene on chromosome 15 (FBN1)
-Fibrillin (glycoprotein) is a constituent of microfibrils providing strength and structure and support for growth factors
characteristics include defect in (Skeletal system, Visual system, Cardiovascular system)
12
Q
distribution of disease marfan’s syndrome
A
- skeletal system (tall, thin build with abnormally long arms and legs, Pectus excavatum, Pectus carinatum, Arachnodactyly)
- eyes (ectopia lentis)
- cardio system (Cystic medial necrosis →dissecting aortic aneurysm, Dilation of aortic ring → aortic valve insufficiency, Mitral valve prolapse)
13
Q
neurofibromatosis
A
- Neurogenic, Schwann cell/PNS tumors
- Type 1 = von Recklinghausen (Chr 17)
- Type 2 (Chr 22) (Acoustic nerve)
- Cutaneous and subcu neurofibromas and café-au-lait spots
14
Q
neurofibromatosis type I
A
- (von Recklinghausen disease)
- 90% of NF
- The cause is mutation in the NF-1 tumor suppressor gene (on chromosome 17)
- Multiple neurofibromas (neurogenic tumors that arise from Schwann cells and other elements of the peripheral nervous system) (3% transform to malignancy)
- Café-au-lait spots
- Iris hamartoma (Lish nodule)
- Skeletal disorder such as scoliosis
- Increases the risk of other tumors (meningioma and pheochromocytoma)
15
Q
neurofibromatosis type II
A
- (bilateral acoustic neurofibromatosis)
- Only 10% of NF
- The cause is mutation in the NF-2 (on chromosome 22) with unknown function
- Neurofibromas
- Café-au-lait spots
- Increases the risk of other tumors (meningioma and ependymomasa)
16
Q
pathophysiology of NF1
A
- Ras: a protein and the gene encoding it
- Ras is a G-protein and act as a proto-oncogene when mutated
- Ras acts as a growth factor receptor on the plasma membrane relaying a signal to a cascade of protein kinases which activate cellular processes including cell growth
- Mutations (Inappropriate activation) in the ras are very common, being found in ~30% of all human tumors.
- Ras has a GTPase reaction that if activated, inhibit ras activity.
- GAP proteins, GTPase-activating proteins can activate ras GTPase activity.
- Ras oncogenes can be activated by point mutations so that its GTPase reaction can no longer be stimulated by GAP – this increases the half life of active ras-GTP mutants
- NF-1 is a tumor suppressor gene which functions as a GAP protein that inactivate ras
- NF-1 mutation in neurofibromatosis will mean that ras is less likely to be inactivated.
- Delayed or impaired inactivation of an oncogene leads to enhanced growth (tumors)
17
Q
inheritance of NF
A
- AD
- 1:3000-4000
- 50% inherited from parent, 50% from NEW mutations
- High prevalence in African Americans
- 2 mutated copies must be present for tumor formation – tumors occur later with acquisition of genetic damage.
18
Q
tx for PKU
A
-low phenylalanine diet
19
Q
PKU
A
-Mutation in a gene for enzyme phenylalanine hydroxylase (PAH) which converts phenylalanine to tyrosine
-Presentation (variable):
brain damage, mental retardation, seizures by 6 months of age
-Accumulation of phenylacetate → mousy or musty sweat and urine odor
-Lack of tyrosine → limited pigmentation
enhanced reflexes (their arm and legs move in a jerky fashion)
-features of maternal PKU are similar to FAS
20
Q
prevalence of PKU
A
- 1:4500 in Ireland; -1:15,000 overall, -1:50,000 in African Americans
- Heterozygous women may have lower rates of miscarriage
- Some evidence that higher levels of phenylalanine may protect against ochratoxin A from certain fungi
- Ochratoxin A associated with spontaneous abortion
21
Q
Tay Sachs
A
- Gangliosidoses, substances from nervous tissue membranes deposited in neurons of CNS, retina.
- Prevalence among Ashkenazi Jews
- Progressive weakness, flaccidity, decreased attentiveness at 6-10 months
- Seizure disorder
- Death < 4 yo
22
Q
x linkage
A
- Recessive pattern of defective alleles on X chromosome.
- 50% chance of transmission by affected female
- Affected males transmit to all daughters
23
Q
Fragile X syndrome
A
- Fragile site on chromosome fails to condense during mitosis
- 2nd MC cause of retardation
- CGG repeat mutation (hundreds to thousands of times)
- Mutation in the FMR-1 gene (familiar mental retardation) which is on X chromosome
- Presentation: Mental retardation, Elongated face with large jaw, Large everted ears, Macro-orchidism, short temper
24
Q
cystic fibrosis
A
- mucoviscidosis
- Most common lethal genetic disorder in Caucasians
- Most common cause of death is pulmonary infection
- Mean survival is 30 years
- Affects, sweat glands, Mucus glands, Lung and, Bronchial tube, Pancreas, Male reproductive system, Liver, GI tract
25
molecular basis for cystic fibrosis
-Gene (CFTR gene) located on chromosome 7
-A normal gene produces a protein called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) with 1440 AAs
-This protein is embedded in cell membrane and it controls the flow of chloride ions → Reduces fluid in glandular secretions when mutated
-In 70%, deletion of the three base pairs that codes for phenylalanine at position 508 is the cause.
-This mutation causes the protein to fold improperly
It is destroyed in the ER before reaching to cell membrane
-causes abnormally thick viscous mucous, which obstructs the duct of exocrine glands
-increased chloride concentration in sweat and tears
26
how CF affects lungs
- Infection with P. aeruginosa (common cause of death) and S. aureus
- Chronic bronchitis
- Bronchiectasis (localized, irreversible dilatation of part of the bronchial tree)
27
how CF affects pancreas
- Plugging pancreatic ducts → atrophy and fibrosis
- Pancreatic insufficiency → Fat and fat-soluble malabsorption
- Malodorous steatorrhea
28
how CF affects male reproductive system
-Obstruction of the vas deferens and epididymis → male infertility
29
how CF affects liver
-Obstruction of the biliary canaliculi → biliary cirrhosis
30
how CF affects GI tract
Small intestinal obstruction (meconium ileus)
31
diagnostic test for CF
-The sweat test is an important diagnostic procedure. Secretion of Cl and Na is normal but their reabsorption by the sweat duct is impaired.
32
where is glycogen stored and degraded
-Glycogen synthesis and degradation occur primarily in liver and skeletal muscle (Cardiac muscle and kidney, store small quantities of glycogen)
33
glycogen metabolism and glycogen storage diseases
- glycogen in the liver is a source of glucose mobilized during hypoglycemia
- Muscle glycogen is stored as an energy reserve for muscle contraction
- Glycogen storage diseases are a group of disorders caused by defects in the synthesis or degradation of glycogen
- Hypoglycemia can lead to lactic acidosis, hyperlipidemia, and hyperuricemia
34
glycogen storage diseases
- von Gierke (hepatorenal glycogenosis) - deficient glucose-6-phosphate
- Pompe - deficient lysosomal alpha-1, 4-glucosidase (debranching enzyme)
- Cori diseases (forbes disease) - deficient alpha-1, 6-glucosyl transferase (debranching enzyme)
- anderson (amylopectinosis) - deficient alpha-1, 4-glucosyl transferase (branching enzyme)
- McArdle - deficient muscle glycogen phosphorylase
- Hers - deficient hepatic glycogen phosphorylase
35
lysosomal storage diseases
- Lysosomes contain many enzymes, each of which removes specific groups from individual sphingolipids
- Genetic deficiency of many of these enzymes are known
- Tay-sachs, Gaucher, Niemann-pick
36
mucopolysaccharidosis
- MPS
- Characterized by deficiency in the lysosomal enzymes required for the degradation of mucopolysaccharides (glycosaminoglycans)
- 1. MPS I (Hurler syndrome): severe form, death by 10 years
- 2. MPS II (Hunter syndrome): milder form, X linked recessive
- Accumulated mucopolysaccharide in both forms are heparan sulfate and dermatan sulfate
- Both clinical features are presented by: MR, Cloudy cornea, Hepatosplenomegaly, Coarse facial features (gargoyle-like feature) and other skeletal deformities, Coronary artery abnormality
37
cholesterol metabolism
- Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesized de novo.
- Most de novo synthesis occurs in the liver from acetyl CoA in the cytoplasm
- HMG-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate limiting enzyme
- Insulin activates and glucagon inhibit this enzyme.
- Cholesterol represses the expression of the HMG-CoA reductase gene and also increase degradation of the enzyme
- 3-hydroxyl 3-methylglutaryl-CoA
38
familial hypercholesterolemia
- Most common inherited disorder (1 in 500)
- Defect: Mutation in LDL receptor gene on chromosome 19
- Mutation causes: Anomalies of receptors for LDL, which causes decreased transport of LDL into cells (Increased level of circulating cholesterol → early atherosclerosis), Loss of feedback inhibition of HMG-CoA reductase, Increased phagocytosis of LDL by macrophage
- Xanthoma: raised yellow lesions filled with lipid-laden macrophage
39
hyperlipidemias
- diabetes, alcoholism, and G6PD deficiency can produce less severe hypertriglyceridemia with increased VLDL and chylomicrons
- Xanthoma: a yellowish-orange, lipid-filled nodule or papule in the skin
40
huntington's disease
- CAG repeat mutation
- Mutation in the Huntington gene that produces abnormal protein, (huntington) which is neurotoxic. → atrophy of caudate nucleus
- Presentation: Early onset of progressive dementia (age 20-50), Choreiform movement
41
muscular dystrophy
- Progressive weakness and loss of muscle tissue
- Autosomal and x-linked forms
- X-linked recessive is more common and cause Duchenne muscular dystrophy
- Disease progresses rapidly
42
duchenne muscular dystrophy
- Gene encodes for dystrophin
| - Stabilizes cell membrane during the stress of muscle contraction
43
Polygenic traits vs multifactorial traits
- Polygenic traits are determined by two or more genes
| - Multifactorial traits are controlled by two or more genes and environment
44
examples of multi-factorial disorders
- Cleft lip or palate
- Clubfoot
- Congenital dislocation of the hip
- Congenital heart disease
- Pyloric stenosis
- Urinary tract malformation
45
types of chromosomal disorders
- Alterations in chromosome number
| - Alterations in chromosome structure
46
Euploid
normal number of chromosomes
47
polyploidy
a chromosome number that is a multiple of the normal diploid set like triploid (3 sets of chromosomes instead of 2 = triploidy)
48
aneuploidy
- a chromosomal number that varies by something less than a set
- Monosomy: having only one member of a homologous pair (2n-1)
- Trisomy: having three copies of a single chromosome (2n+1)
49
autosomal aneuploidy
- Autosomal monosomy is a lethal condition
- Autosomal trisomy most of the time are lethal
- Only trisomies 8, 13, 18, and 21 result in live birth:
- Trisomy 8: Wakany syndrome (47, +8)
- Trisomy 13: Patau syndrome (47,+13)
- Trisomy 18: Edwards syndrome (47,+18)
- Trisomy 21: Down syndrome (47,+21)
50
patau syndrome
- (47,+13)
- Mean survival time 1 month
- Parental age only known risk factor
- Mental retardation
- Cleft lip and/or palate
- Cardiac defect
- Renal abnormalities
- Microcephaly!!
- Polydactyly
51
edwards syndrome
- (47,+18)
- Average survival time 2–4 months
- For unknown reasons 80% of all trisomy 18 are female
- maternal age is a risk factor
- Small at birth and grow slowly
- Mental retardation
- Low set ears
- Micrognathia (small chin)
- Congenital heart disease
- Overlapping flexed fingers
- Rocker-bottom feet (the bottom of the feet is like a rocker chair!)
52
down syndrome
- 47, +21
- First chromosomal abnormality discovered in humans (1959)
- Is the only autosomal trisomy that allows survival into adulthood
- Most common of the chromosomal disorder
- 1/900 live births
- Leading cause of inherited mental retardation in US
- Leading cause of heart defects in US (40% chance of congenital heart defects)
53
clinical findings in down syndrome
- Wide flat face
- Broad short neck
- Low-bridged nose
- Epicanthal folds = skin folds in the inner corner of the eyes
- Brushfield spots = spots on the irises (speckled appearance)
- Palmar (simian) crease = a single crease and thick, furrowed tongues
- Congenital heart disease
- Duodenal atresia (“double-bubble sign”)
- Hirschsprung disease (a congenital aganglionic megacolon: no movement causes bowel obstruction → megacolon)
- Increased risk (15-20×) of ALL (acute lymphocytic leukemia)
- Increased risk of Alzheimer disease (by 40 virtually all will develop Alzheimer disease)
54
Risk for autosomal trisomy
- Advanced maternal age
- Under age 25, 1 in 2000
- Risk increases rapidly after 35 years of age
- 1 in 250 at age 35
- 1 in 100 at age 40
55
sex chromosome aneuploidy
- 45, X Turner’s syndrome
- 47, XXY Klinefelter syndrome
- 47, XYY XYY syndrome
56
turner's syndrome
-45, X
-No Barr body present
-Is the only monosomy compatible with life
98% of all fetuses with the syndrome are spontaneously aborted (hydrops fetalis)
-Complete absence of an X chromosome is lethal --> NO MEN WITH TURNERS
-The second X chromosome is required for normal development of ovary and oogenesis → rudimentary ovaries (atrophic “streaked” ovaries) = gonadal dysgenesia
-Primary amenorrhea
-Infertility
-Failure to develop secondary sex characteristic
-Common cause of female hypogonadism
57
clinical presentation of turners
- Females; short, wide chest
- Cystic hygroma (dilation of lymphatic channels) and web neck
- Hypothyroidism
- Puffiness of hands and feet
- Preductal coarctation of the aorta
- Bicuspid aortic valve
- NO MENTAL DYSFUNCTION
58
Klinefelter syndrome
- 47, XXY
- Features do not develop until after puberty
- Other forms 48, XXYY, 48, XXXY and 49, XXXXY
- Common cause of male hypogonadism → (LH and FSH increase, Testosterone decreases)
- The more X, the more chance of mental retardation!
- Infertility due to azoospermia --> testicular atrophy
- Eunuchoid body habitus
- High pitched voice
- Female distribution of hair
- Gynecomastia
59
XYY syndrome
- 47, XYY
- above average height
- no established link with possible antisocial behavior
60
triploidy
- Three sets of chromosomes (69)
- Most common form of polyploidy
- 1% conceptions are triploid but 99% die before birth.
61
cri du chat syndrome
- 45 XX, 5p- or 45 XY, 5p-
- High pitched cat like cry
- Mental retardation
- Congenital heart defect
- Microcephaly
62
retinoblastoma
- deletion of chromosome
| - 13q14
63
wilms tumor
- deletion of chromosome
| - 11q13
64
teratogenic agents
- produce abnormalities during embryonic or fetal development
- Radiation
- Chemicals and drugs (Fetal alcohol syndrome, Cocaine babies, Folic acid deficiency)
- Infectious agents
65
criteria for defining fetal alcohol syndrome
- prenatal or postnatal growth retardation (weight or length below 10th percentile)
- Central nervous system involvement (Neurologic abnormalities, Developmental delays, Behavioral dysfunction, Intellectual impairment, Skull and brain malformation)
- characteristic face (Short palpebral fissures (eye openings), Thin upper lip, Elongated, flattened midface and philtrum)
66
effects of cocaine use during pregnancy
- Decrease in uteroplacental blood flow
- Maternal hypertension
- Stimulation of uterine contractions
- Fetal vasoconstriction
67
methods used for fetal diagnosis
- Maternal blood screening
- Ultrasonography
- Amniocentesis
- Chorionic villus sampling
- Percutaneous umbilical fetal blood sampling
- Fetal biopsy
- Cytogenic and biochemical analyses
