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Physio Genetics > Genetic and Congenital Disorders > Flashcards

Genetic and Congenital Disorders Flashcards

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1
Q

causes of birth defects

A
  • genetic factors
  • environmental factors
  • intrauterine factors (rare)
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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

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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
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4
Q

intrauterine factors causing birth defects

A

-fetal crowding, positioning, or entanglement of fetal parts with the amnion

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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

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6
Q

autosomal recessive vs. dominant - onset

A
  • R: early uniform onset (infancy/childhood)

- D: variable onset (may be delayed into adulthood - HD)

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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

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8
Q

autosomal recessive vs. dominant - penetrance

A
  • R: complete penetrance

- D: incomplete penetrance with variable expression

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9
Q

autosomal recessive vs. dominant - mutation

A
  • R: usually an enzyme protein

- D: usually a structural protein or receptor

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10
Q

autosomal recessive vs. dominant - requires

A
  • R: mutation of both alleles

- D: mutation of one allele

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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)

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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)
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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
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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)
    1. Multiple neurofibromas (neurogenic tumors that arise from Schwann cells and other elements of the peripheral nervous system) (3% transform to malignancy)
    1. Café-au-lait spots
    1. Iris hamartoma (Lish nodule)
    1. Skeletal disorder such as scoliosis
    1. Increases the risk of other tumors (meningioma and pheochromocytoma)
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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)
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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)
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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.
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18
Q

tx for PKU

A

-low phenylalanine diet

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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

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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
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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
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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
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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
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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
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25
Q

molecular basis for cystic fibrosis

A

-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

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26
Q

how CF affects lungs

A
  • Infection with P. aeruginosa (common cause of death) and S. aureus
  • Chronic bronchitis
  • Bronchiectasis (localized, irreversible dilatation of part of the bronchial tree)
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27
Q

how CF affects pancreas

A
  • Plugging pancreatic ducts → atrophy and fibrosis
  • Pancreatic insufficiency → Fat and fat-soluble malabsorption
  • Malodorous steatorrhea
28
Q

how CF affects male reproductive system

A

-Obstruction of the vas deferens and epididymis → male infertility

29
Q

how CF affects liver

A

-Obstruction of the biliary canaliculi → biliary cirrhosis

30
Q

how CF affects GI tract

A

Small intestinal obstruction (meconium ileus)

31
Q

diagnostic test for CF

A

-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
Q

where is glycogen stored and degraded

A

-Glycogen synthesis and degradation occur primarily in liver and skeletal muscle (Cardiac muscle and kidney, store small quantities of glycogen)

33
Q

glycogen metabolism and glycogen storage diseases

A
  • 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
Q

glycogen storage diseases

A
  • 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
Q

lysosomal storage diseases

A
  • 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
Q

mucopolysaccharidosis

A
  • 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
    1. 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
Q

cholesterol metabolism

A
  • 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
Q

familial hypercholesterolemia

A
  • 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
Q

hyperlipidemias

A
  • 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
Q

huntington’s disease

A
  • 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
Q

muscular dystrophy

A
  • 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
Q

duchenne muscular dystrophy

A
  • Gene encodes for dystrophin

- Stabilizes cell membrane during the stress of muscle contraction

43
Q

Polygenic traits vs multifactorial traits

A
  • Polygenic traits are determined by two or more genes

- Multifactorial traits are controlled by two or more genes and environment

44
Q

examples of multi-factorial disorders

A
  • Cleft lip or palate
  • Clubfoot
  • Congenital dislocation of the hip
  • Congenital heart disease
  • Pyloric stenosis
  • Urinary tract malformation
45
Q

types of chromosomal disorders

A
  • Alterations in chromosome number

- Alterations in chromosome structure

46
Q

Euploid

A

normal number of chromosomes

47
Q

polyploidy

A

a chromosome number that is a multiple of the normal diploid set like triploid (3 sets of chromosomes instead of 2 = triploidy)

48
Q

aneuploidy

A
  • 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
Q

autosomal aneuploidy

A
  • 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
Q

patau syndrome

A
  • (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
Q

edwards syndrome

A
  • (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
Q

down syndrome

A
  • 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
Q

clinical findings in down syndrome

A
  • 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
Q

Risk for autosomal trisomy

A
  • 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
Q

sex chromosome aneuploidy

A
  • 45, X Turner’s syndrome
  • 47, XXY Klinefelter syndrome
  • 47, XYY XYY syndrome
56
Q

turner’s syndrome

A

-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
Q

clinical presentation of turners

A
  • 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
Q

Klinefelter syndrome

A
  • 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
Q

XYY syndrome

A
  • 47, XYY
  • above average height
  • no established link with possible antisocial behavior
60
Q

triploidy

A
  • Three sets of chromosomes (69)
  • Most common form of polyploidy
  • 1% conceptions are triploid but 99% die before birth.
61
Q

cri du chat syndrome

A
  • 45 XX, 5p- or 45 XY, 5p-
  • High pitched cat like cry
  • Mental retardation
  • Congenital heart defect
  • Microcephaly
62
Q

retinoblastoma

A
  • deletion of chromosome

- 13q14

63
Q

wilms tumor

A
  • deletion of chromosome

- 11q13

64
Q

teratogenic agents

A
  • produce abnormalities during embryonic or fetal development
  • Radiation
  • Chemicals and drugs (Fetal alcohol syndrome, Cocaine babies, Folic acid deficiency)
  • Infectious agents
65
Q

criteria for defining fetal alcohol syndrome

A
  • 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
Q

effects of cocaine use during pregnancy

A
  • Decrease in uteroplacental blood flow
  • Maternal hypertension
  • Stimulation of uterine contractions
  • Fetal vasoconstriction
67
Q

methods used for fetal diagnosis

A
  • Maternal blood screening
  • Ultrasonography
  • Amniocentesis
  • Chorionic villus sampling
  • Percutaneous umbilical fetal blood sampling
  • Fetal biopsy
  • Cytogenic and biochemical analyses

Physio Genetics (5 decks)

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