Genetic and Congenital Disorders Flashcards
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)
neurofibromatosis
- 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)
- 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)
neurofibromatosis type II
- (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)
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
- 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.
tx for PKU
-low phenylalanine diet
PKU
-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
- 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
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
mucopolysaccharidosis
- MPS
- Characterized by deficiency in the lysosomal enzymes required for the degradation of mucopolysaccharides (glycosaminoglycans)
- MPS I (Hurler syndrome): severe form, death by 10 years
- 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
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
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
- Clubfoot
- 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
Euploid
normal number of chromosomes
polyploidy
a chromosome number that is a multiple of the normal diploid set like triploid (3 sets of chromosomes instead of 2 = triploidy)
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)
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
- (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
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!)
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
-Infertility
-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
- Hypothyroidism
- Puffiness of hands and feet
- Preductal coarctation of the aorta
- Bicuspid aortic valve
- NO MENTAL DYSFUNCTION
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
XYY syndrome
- 47, XYY
- above average height
- no established link with possible antisocial behavior
triploidy
- 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
- Microcephaly
retinoblastoma
- deletion of chromosome
- 13q14
wilms tumor
- deletion of chromosome
- 11q13
teratogenic agents
- produce abnormalities during embryonic or fetal development
- Radiation
- 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
- Ultrasonography
- Amniocentesis
- Chorionic villus sampling
- Percutaneous umbilical fetal blood sampling
- Fetal biopsy
- Cytogenic and biochemical analyses
