Genetic and Congenital Disorders Flashcards Preview

3 - Physio Genetics > Genetic and Congenital Disorders > Flashcards

Flashcards in Genetic and Congenital Disorders Deck (67):

causes of birth defects

-genetic factors
-environmental factors
-intrauterine factors (rare)


genetic factors causing birth defects

-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


environmental factors causing birth defects

-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


intrauterine factors causing birth defects

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


single-gene disorders

-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


autosomal recessive vs. dominant - onset

-R: early uniform onset (infancy/childhood)
-D: variable onset (may be delayed into adulthood - HD)


autosomal recessive vs. dominant - pattern

-R: requires 2 mutant alleles, may "skip" generations
-D: usually inherited from affected parent, sporadic cases possible


autosomal recessive vs. dominant - penetrance

-R: complete penetrance
-D: incomplete penetrance with variable expression


autosomal recessive vs. dominant - mutation

-R: usually an enzyme protein
-D: usually a structural protein or receptor


autosomal recessive vs. dominant - requires

-R: mutation of both alleles
-D: mutation of one allele


Marfan's syndrome

-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)


distribution of disease marfan's syndrome

-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)



-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


neurofibromatosis type I

-(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)
-2. Café-au-lait spots
-3. Iris hamartoma (Lish nodule)
-4. Skeletal disorder such as scoliosis
-5. Increases the risk of other tumors (meningioma and pheochromocytoma)


neurofibromatosis type II

-(bilateral acoustic neurofibromatosis)
-Only 10% of NF
-The cause is mutation in the NF-2 (on chromosome 22) with unknown function
-Café-au-lait spots
-Increases the risk of other tumors (meningioma and ependymomasa)


pathophysiology of NF1

-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)


inheritance of NF

-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.


tx for PKU

-low phenylalanine diet



-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


prevalence of PKU

-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


Tay Sachs

-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


x linkage

-Recessive pattern of defective alleles on X chromosome.
-50% chance of transmission by affected female
-Affected males transmit to all daughters


Fragile X syndrome

-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


cystic fibrosis

-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


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


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)


how CF affects pancreas

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


how CF affects male reproductive system

-Obstruction of the vas deferens and epididymis → male infertility


how CF affects liver

-Obstruction of the biliary canaliculi → biliary cirrhosis


how CF affects GI tract

Small intestinal obstruction (meconium ileus)


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.


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)


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


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


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



-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


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


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



-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


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


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


duchenne muscular dystrophy

-Gene encodes for dystrophin
-Stabilizes cell membrane during the stress of muscle contraction


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


examples of multi-factorial disorders

-Cleft lip or palate
-Congenital dislocation of the hip
-Congenital heart disease
-Pyloric stenosis
-Urinary tract malformation


types of chromosomal disorders

-Alterations in chromosome number
-Alterations in chromosome structure



normal number of chromosomes



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



-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)


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)


patau syndrome

-Mean survival time 1 month
-Parental age only known risk factor
-Mental retardation
-Cleft lip and/or palate
-Cardiac defect
-Renal abnormalities


edwards syndrome

-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!)


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)


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)


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


sex chromosome aneuploidy

-45, X Turner’s syndrome
-47, XXY Klinefelter syndrome
-47, XYY XYY syndrome


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
-Failure to develop secondary sex characteristic
-Common cause of female hypogonadism


clinical presentation of turners

-Females; short, wide chest
-Cystic hygroma (dilation of lymphatic channels) and web neck
-Puffiness of hands and feet
-Preductal coarctation of the aorta
-Bicuspid aortic valve


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


XYY syndrome

-47, XYY
-above average height
-no established link with possible antisocial behavior



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


cri du chat syndrome

-45 XX, 5p- or 45 XY, 5p-
-High pitched cat like cry
-Mental retardation
-Congenital heart defect



-deletion of chromosome


wilms tumor

-deletion of chromosome


teratogenic agents

-produce abnormalities during embryonic or fetal development
-Chemicals and drugs (Fetal alcohol syndrome, Cocaine babies, Folic acid deficiency)
-Infectious agents


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)


effects of cocaine use during pregnancy

-Decrease in uteroplacental blood flow
-Maternal hypertension
-Stimulation of uterine contractions
-Fetal vasoconstriction


methods used for fetal diagnosis

-Maternal blood screening
-Chorionic villus sampling
-Percutaneous umbilical fetal blood sampling
-Fetal biopsy
-Cytogenic and biochemical analyses