Pathophysiology – EXAM IV
An exam IV survival guide, hope this helps. (*) indicates it will be covered in Monday’s lecture, so the material I used came from the notes as is.
Rock on,
-Pat Clements
Codominance?
Achondroplasia
- autosomal dominant trait
- most adults are heterozygotes (homozygotes don’t survive)
- gain of function mutation in fibroblast growth factor receptor 3 (FGFR3)
à arginine substitution (i.e. for glycine)
à abnormal endochondral ossification
- dwarfism with disproportionate arms and legs
- abnormal pelvis, neuro and cardiopulmonary problems, hearing loss, spine deform
- somatotrophin (synthetic human growth hormone) can treat, in early years
Albinism
- lack of pigmentation
- defect is autosomal recessive
- defect in tyrosinase gene (catalyzes the reactions necessary to make dark pigment)
- heterozygous has normal phenotype, must be homozygous aa to have condition.
Angleman’s syndrome (aka Happy Puppet Syndrome)
- most patients have deletion in the AS region of maternal chromosome 15
- some have paternal uniparental disomy for chromosome 15
- few (3%) have defect in maternal imprinting
- candidate gene: UBE3A - transfers ubiquitin to protein
- targets protein for breakdown by proteasome
- characterized by mental retardation, speech impairment, excitability, inapprop. laughter
- unsteady gait and unsteady limbs
Anhidrotic extodermal dysplasia
- mosaicism, resulting from incomplete X-inactivation in females
- mutant X chromosome gene à lack sweat glands
- use electrochemical resistance test to find areas of skin that are mutant
Aniridia
- caused by a PAX6 mutation
- absence of the iris
Ataxia Telangiectasia
- a disease of DNA repair (nothing else mentioned in lecture)
Becker Muscular Dystrophy (see DMD)
Bloom’s syndrome
- defect in BLM helicase (but other helicases not affected)
à helicase works to unwind tetraplex DNA structures
- leads to chromosomal and genetic instability
Causes: Growth retardation Sunlight sensitivity
Decreased fertility Immunodeficiency
Cancer (both solid tumors and leukemias)
Bruton’s agammaglobulinemia
- defective tyrosine kinase à defective maturation of B-cells
à no Ig production à bacterial infection susceptibility at 4-8 months
(initially ok, b/c antibodies from mother’s breastmilk)
Campomelic dysplasia
- mutant SOX9 gene (homologies to SRY, sex determining region of Y chromosome)
- underdeveloped thorax, bent limbs
- sex reversal (i.e. female with XY karyotype)
Chronic atrophic gastritis – see pernicious anemia
Complete Androgen Insensitivity Syndrome (Testicular Feminization)
- XY female
- has testicular tissue (secretes androgens
- but defective androgen receptor à androgen insensitive
- phenotypically normal female, with some abnormalities
Congenital Adrenal Hyperplasia
- defect. adrenal cortex à overproduction of androgens à virilization of female infants
- often caused by deficiency 21 hydroxylase
Craniosynostosis
- caused by Fibroblast growth factor response genes (cell division/migrat/diff.)
- mutant FGFR 2
- irregular shape of skull
- i.e. Crouzon syndrome and Apert syndrome
Cri du Chat syndrome
- caused by deletion of the p region of chromosome 5
- classified as a contiguous gene syndrome (segmental aneusomy syndrome)
- characteristic “cat cry” in newborns, caused by a pharyngeal defect
- the following webpage has a link to hear what the cry sounds like, and other info
http://www.criduchat.asn.au/criduchat/video.htm
* Cystic Fibrosis
- autosomal recessive disorder (“horizontal” inheritance, heterozygotes not affected)
- single gene mutation, involving a 3 BP deletion (therefore in frame), Δ508 common
- mutant cystic fibrosis transmembrane regulator gene (CFTR)
- abnormal regulation of chloride ion passage through endothelial cells
- In skin, CFTR normally keeps Cl- ions out of sweat ducts
- mutant increased NaCl in sweat à “salty sweat” diagnosis
- In endoth. cells lining airways, Cl- not transported out of cells
à Na rushes in, followed by water à highly dehydrated mucus
- causes lower airway inflammation and infection, chronic breathing difficulties
- GI reabsorption problems, diabetes mellitus, defective pancreatic secretion, cirrhosis
- azoospermia, lack of vas deferens in men
- also decreased fertility in women
- average survival age of 33 yrs.
- more common in Caucasians
- no good molecular test for CF
DiGeorge anomaly of brachial arch defects (related to the other DiGeorge stuff below???)
- defect in thymus development (site of T-cell differentiation and selection)
à leads to T-cell deficiency
à susceptible to yeast and viral infections
DiGeorge Velocardiofacial syndrome
- actually a combo of 3 sydromes: DiGeorge Syndrome (DGS)
Conotruncal anomalies face (CTAF)
Velocardiofacial syndrome (VCFS)
- deletion in DiGeorge Syndrome critical region (DSCR) – [chromosome 22]
- Cardiac problems are the most life threatening
- also cognitive impairments and neonatal hypocalcemia
Down syndrome – see trisomy 21
* Duchene muscular dystrophy (DMD)
- x-linked recessive trait
- apparent non-carrier mother might produce offspring with germline mosaics
- increased risk of child passing on to their progeny
- carrier females are normal
- mutation in the dystrophin gene at Xp21
- the largest human gene
- most common mutation is deletion, though duplication or bad splicing also poss.
- frameshift mutation à absent protein
- dystrophin mainly found in skeletal, heart, smooth muscle tissue
- interfaces between cytoskeletal proteins and group transmembrane proteins
- protein helps maintain muscle calcium permeability
- also acts as shock absorber (prevents damage when fibers contract)
- characterized by progressive myopathy (muscle wasting), starting at age 3-5
- death at age 20-25 from respiratory failure
* Becker muscular dystrophy (BMD)
- less severe progressive myopathy than DMD, less common than DMD
- truncating mutations at Xp21
- in-frame mutation à partially functioning dystrophin protein
- typically later onset than DMD
- Molecular Testing:
- Immunofluorescence staining for dystrophin protein in muscle sample
- PCR amplification of gene
Edward’s syndrome – see trisomy 18
Emphysema
- environmental factors can influence genes
- α1-anti-trypsin, coded by the Serpina genes (multiple alleles)
-blocks degradation of proteins (inhibits trypsin and elastase)
- smoking introduces superoxide anion à inhibits this enzyme à can’t protect
à breakdown of structural proteins à emphysema
Faconi Anemia
- bone marrow failure, growth retardation
- skin, G.I., and kidney abnormalities
- increased cancer occurrences, particularly myolegnous leukemia
- increased chromosome damage (more susceptible)
- defect in a Faconi complementation group
à possibly knocks out important signal or repair pathway
* Factor V Leiden Trhombophilia
- single point mutation in factor V gene at nucleotide 1691
- Gà A base substitution leads to Arginine à to histidine
- occurs at an APC cleavage site (therefore Activated Protein C resistance)
- causes slower inactivation of Factor V by APC
à increases thrombin production
- increased risk of clotting (thrombosis)
- heterozygotes have slightly elevated risk
- detect mutation by MnI 1 enzyme digestion
(mutants have one less cleavage site, so produces 2 DNA fragments instead of 3)
Fetal Alcohol syndrome
- teratogen = ethanol
- causes low birthweight, growth delay, heart defects
Fetal Dilantin syndrome
- teratogen – dilantin (anti-epileptic drug)
- causes hypertelorism, short nose and low nasal bridge
Favism
- example of ecogenetics
- decreased activity in glucose-6-phosphate dehydrogenase
à less reduced glutathione à oxid. damage to RBC’s
- oxidant drugs can accelerate loss of glutathione
- or ingestion of fava beans
- So is it just me, or does half of what we learned in block 1 relate to Silence of the Lambs?
Folate deficiency - see homocysteinemia, neural tube defects, megaloblastic anemia
Fragile X syndrome
- classified as a DNA repeat expansion disorder, loss of function
- most common inherited form of mental retardation (remember, trisomy 21 is common, yet it is not caused by the inheritance of a specific gene, but rather by having an extra whole chromosome)
- some have mild facial dysmorphic features, while others have no symptoms at all
- self-injurious, hyperactive, and impulsive behaviors most common
- fragile site contains a CGG sequence, repeated in the 5’ region of FMR1 gene
- repeat occurs upstream of the start codon
- FMR1 encodes an RNA binding protein that interacts with polyribosomes
- with disease, characteristic low expression in brain and testes
- more repeats à greater inactivation (b/c highly unstable during mitosis)
(6-50 repeats is normal, 50-200 is permutation, 200+ is full mutation)
- repeats due to uneven crossing over or amplification b/c of defect replication
- repeats accumulate over generations
- to test for fragile X, run PCR of FMR gene, then separate using electrophoresis
- look for large DNA sequence (won’t move far in the gel)
Galactosemia
- autosomal recessive, equal gender and race ratios
- can’t metabolize galactose (serum levels higher than 3-4 mg/dl)
- defective galactokinase or uridine diphosphate hexose-4-epimerase
- Most common – defect galactose-1-phosphate uridyltransferase
- can’t convert to UDP-galactose and glucose-1-P
- severity depends on type of variant
- buildup of galactisol (toxic)
- causes cataracts, jaundice, liver enlargement
- TREAT: - restrict galactose in diet (i.e. milk)
Gout
- defective purine metabolism à excess uric acid
- Sodium urate crystal deposits in joints à painful attacks, often in toes
- multiple possible causes:
- defective PRPP synthase à can’t be regulated à oversynth of purines à
therefore many broken down)
- defective glucose-6-phosphatase à increased G6P à inc Ribose 5-P via PPP
à therefore oversynthesis of purines
- partial HGPRTase deficiency à can’t salvage purines properly à inc uric acid
(Gout is not actually caused by the evil gout demon with the stingray barb tail)
- Follow this link for an 18th century newspaper editorial regarding the treatment of gout
http://www.infopt.demon.co.uk/grub/gout.htm
Hand-foot-genital syndrome
- caused by HOX-A13 mutation
- just like it sounds, defects in the hands, feet, and genitals
* Hereditary Hemochromatosis
- iron overload disorder (transferrin saturation, increased serum ferritin)
- autosomal recessive trait, but phenotype is sex-influenced
- less common in females
(possibly b/c of less dietary iron uptake and losses via menstruation)
- molecular testing on HFE gene (common: C282Y and H63D mutations)
- HFE facilitates transferrin-bound iron uptake from gut
- if mutant, cell fails to sense circulating T.F.-bound iron
à increased absorption of dietary iron
à high expression of iron transporters, but low ferritin expression
- heterozygotes have elevated serum iron, but no major iron overload complications
- takes long time to develop pathology
- especially toxic to liver and kidneys
Hemophilia A
- X-linked recessive
- higher incidence in males (since hemizygous)
- deficient in factor VIII (clotting factor)
- traced in royal families of Europe
Hereditary Orotic Anemia
- caused by two deficiencies: à can’t make pyrimidines
- orotidine-5-P phosphorylase
- orotidine-5-P decarboxylase
- leads to decreased UTP (inhibitor of the pathway)
à high flux through à increased orotic acid
-Treatment: uridine
(+ kinase) à UMP à UDP à UTP synthesis à can downregulate pathway
Hermaphroditism (2 classifications)
PSUEDO: - XX male w/ gonadal dysgenesis (can’t undergo puberty)
- SRY factor was transferred to X chromosome
TRUE: - 46, XX
- has both testicular and ovarian tissue, both sex organs, or ambiguous
Heterogeneous Nonpolyposis Colon Cancer
- a disease of DNA repair (nothing else mentioned in lecture)
HIV (Human Immunodeficiency Virus)
- great variety among viruses b/c lacks reverse transcriptase 3’-5’ exonuclease activity
- polycistronic nuclear material, RNA spliced after transcription
à target for protease inhibitors!
Homocystinuria
- autosomal recessive
- homocysteine is produced from methionine.
- Classical Homocystinuria - defect serine cystathione synthase (chromosome 21)
- can’t covert homocysteine à cystathione
- also disease with B12 deficiency
- can’t re-methylate homocyteine to form methionine
- Methionine synthase deficiency
- converta homocysteine to methionine (requires methyl-THF cofactor)
- blocks the reconversion of methyl-THF à THF
- Characterized by developmental delay, childhood osteoporosis, myopia & ectopia lentis
- increased CHD (increased thrombus risk)
- TREAT with folic acid, pyroxidine
- restrict methionine in diet, and supplement cysteine.
Huntington’s Disease
- single gene mutation
- classified as a DNA repeat expansion disorder
- autosomal dominant (“vertical” inheritance, heterozygotes are affected)
- expansion of CAG repeat in the coding region for the protein Huntingtin
à causes a polyglutaminyl chain to be added (gain of function)
- extra glutamines causes Huntingtin aggregation in brain cell nuclei
- binds to Huntingtin associated protein (HAP) in brain
- later onset, usually well into reproductive age (30-50 years old)
- all heterozygotes will eventually express phenotype
- 50% express it by age 50
- chorea (abnormal voluntary movement)
- dementia (basal ganglia atrophy and dilation of lateral ventricle)
(degredation in cerebral cortex and basal ganglia)
Hyperammonemia
- autosomal recessive, equal gender ratios
- disorder of urea cycle, many enzyme deficiencies possible
- most common – deficient ornithine transcarbamylase
- can’t convert carbamoyl phosphate à citrilline, for shuttle out of mitochondria
- anorexia, hypothermia, edema, respiratory problems, tremors, poor coordination
- TREAT: - stop protein uptake
- supplement non-protein calories
- dialysis
Hyperphenylalaninemia
- autosomal recessive (equal gender ratios, but racial differences exist)
- generally classified with serum phenylalanine higher than 2mg/dl
- Classical Phenylketonuria Hyperphenylalaninemia (most common)
- caused by lack of phenyalanine-4-hydroxylase [PAH] (can’t catabolize)
- allelic heterogeneity allows for different levels of enzyme (different severities)
- Non-classical PKU (BH4 deficiency hyperphenylalaninemia)
- deficiency in tetrahydrobiopterin (BH4)
- this is a necessary cofactor for PAH
Hyperphenylalaninemia characterized by:
- increased serum phenylalanine
- decreased tyrosine, melanin, fumarate, and catecholamines
- irritability, eczema-like rash, musty urine odor
- microcephaly, mental retardation
- TREAT: - supplement BH4 and tyrosine
- avoid high protein foods
- high carbs and fats instead for energy