Genetic Disorders (from Pathology) Flashcards
Autosomal Dominant Diseases
- ADPCK
- Huntington Chorea
- Marfan Syndrome
- Familial hypocholesterolema
- Osteogenesis Imperfecta
- Achondroplasia short-limed dwaris
Autosomal Recessive Diseases
- Lysosomal Storage Diseases
- Sickle Cell anemia
- Cystic fibrosis
- Tay sachs
- Glycogen storage disease
- Mucopolysaccharidoses (Hurler, Hunter syndromes)
Autosomal Chromosome (Cytogenetic) Disorders
- Trisomy 21
- Trisomy 13 (Patau)
- Trisomy 18 (Edward)
Sex Chromosome (Cytogenetic) Disorders
- Kleinfelter Syndrome
- Turner Syndrome
- Triple XXX
- XYY
X-Linked Recessive Diseases
- Duchenne Muscular Dystrophy
X-linked Dominant Diseases
- Fragile X
- Rett syndrome
ADPCK
- Definition:
- Etiolathogenesis: autosomal dominant mutation in PKD1 and 2, which encode for polycystin
- Clinical: cysts in kidney, pancreas, spleen, lung, aneurysm of circle of Willis
Huntington Chorea
- **Definition: **autosomal dominant disease characterized by progressive movement disorders and dementia
- **Etiopathogenesis: **unstable CAG repeats in HTT, toxic gain of function in the protein, high penetrance, shows anticipation in following generations
- **Clinical: **movement disorders, dementia
Marfan Syndrome
- Definition: autosomal dominant disorder characterized by skeletal abnormalities
- Etiopathogenesis: defect in extracellular glycoprotein fibrillin-1 due to mutations of *FBN1 *or FBN2
- **Clinical: **
- skeletal- pectus, scoliosis, joint laxity, arachnodactility, tall stature, long extremities
- cardio- aortic dilation, cystic medionecrosis, mitral valve prolapse
- ocular- ectopia lentis
Sickle Cell Anemia
- **Definition: **autosomal recessive disorder characterized by formation of sickled RBCs
- **Etiopathogenesis: **point missense mutation in Hemoglobin A which changed glutamic acid into valine, causes new hydrophobic patch which causes aggregation of hemoglobin; sickled cells cannot move thru capillaries well, causes hypoperfusion and blood vessel occlusion
- **Clinical: **heterozygotes: have protective factor for malaria
Mucopolysaccharidosis IH (Hurler Syndrome)
- Definition: lysosomal storage disease
- Etiopathogenesis: autosomal recessive, deficiency in alpha-1-iduronidase enzymes, accumulates heparan, sulfate, dermatan sulfate, mucopolysaccharides in mononuclear phagocytes, fibroblasts, endothelial cells
- Clinical: coarse facial features, hepatosplenomegaly, corneal clouding, valve and subendothelial arterial thickening, mental retardation
Familial Hypercholesterolemia
- **Definition: **autosomal dominant hyperlipidemia disorder
- Etiopathogenesis: mutation in LDL receptor, elevated serum cholesterol
- **Clinical: **early onset atherosclerosis
Kleinfelter Syndrome
- **Definition: **sex chromosome hypogonadism disorder in males
- **Etiopathogenesis: **47, XXY; meotic non-disjunction
- **Clinical: **tall stature, gynaecomastia, infertility, mild learning difficulties, eunuchoid body habitus, no male secondary sex characteristics, atrophic testes, FSH and estrogen elevated, low testosterone
Turner Syndrome
- **Definition: **sex chromosome hypogonadism disorder in females
- **Etiopathogenesis: **45, X, partial or complete monosomy of shot arm of X chromosome
- **Clinical: **short stature, low posterior hairline, webbing of neck, coarctation of aorta, streak ovaries, infertility, amenorrhea, peripheral lymphedema at birth
Trisomy 21 (Down Syndrome)
- Definition: chromosomal disorder where chromosome 21 has an extra copy
- **Etiopathogenesis: **
- 47, XY or XX, +21** caused **by meiotic nondisjunction
- 46, XY or XX,der(14;21)(q10;q10), +21 robertsonian translocation
- 46, XX or XY/ 47, XX or XY, +21 mosaic caused by mitotic nondisjunction in embryogenesis
- Epidemiology: 47 XY, +21 heavily infuenced by maternal age
- **Clinical: **mental retardation, epicathic folds, flat facial profile, simian crease, congential heart defects, Alzheimer’s, acute megakaryoblastic leukemia
Trisomy 18
- **Definition: **chromosomal disorder where chromosome 18 has an extra copy
- **Etiopathogenesis: **
- 47, XX or XY, +18 meiotic nondisjunction
- 46, XX or XY/ 47, XX or XY, +18 mitotic nondisjunction
- Clinical: mental retardation, low set ears, congential heart defects (ventricular septal defect), horseshoe kidney, rocker bottom feet
Trisomy 13
- **Definition: **chromosomal disorder where chromosome 13 has an extra copy
-
Etiopathogenesis:
- 47, XX or XY, +13 meiotic nondisjunction
- translocation type (chromosomes 13 and 14)
- mosaic type
- **Clinical: **microphthalmia, microencephaly, mental retardation, polydactly, cleft lip and palate, cardiac defects, umbilical hernia, rockerbottom feet, most children die in first year
Wiliams Syndrome
- **Definition: **gene mutation disease
- **Etiopathogenesis: **microdeletion in chromosome 7
- **Clinical: **distinct facial appearence, cardiovascular abnormalities, mental retardation, distinctive congitive profile
Tay Sachs
- **Definition: **autosomal recessive lysosomal storage disease
- **Etiopathogenesis: **autosomal recessive, mutations in hexosaminidase, neurons rich in galgiosides, lipid accumulation in retinal ganglion cells
- Epidemiology: found in Ashkenzazi Jews
- **Clinical: **motor and mental deterioration, death age 2-3yrs neuronal ballooning & destruction, cherry red macular choroid
Osteogenesis Imperfecta
- **Definition: **autosomal dominant collagen disorder
- **Etiopathology: **type I and II caused by mutations in alpha-1 collagen
- **Clinical: **brittle bones, loose joints, type II: severe respiratory problems and early death
Duchenne Muscular Dystrophy
- **Definition: **sex chromosome genetic disorder that causes muscular degeneration
- **Etiopathogenesis: **X-linked recessive mutation in dystrophin, protein that provides structural stability in muscle cell membranes
- **Clinical: **proximal muscle weakness, muscle wasting
PCR
- method used for molecular genetic diagnosis that amplifies target DNA
- requires DNA template, oligonucleotide primers, thermostable polymerase, deoxynucleotides, magnesium-containing buffers
- Steps
- DNA template heated to denature
- cooled to hybridize and anneal primers
- mixture warmed to allow synthesis and extention of the sequences
- products analyzed via
- amplicon length analysis in gel electrophoresis (ex. triplet repeat disorders in Fragile X, Huntington’s)
- restriction fragment length analysis (ex. hereditary hemochromatosis)
- direct sequencing
Restriction Endonucleases (Enzymes)
- method used for molecular genetic diagnosis that uses bacterially-derived endonucleases to cleave DNA at specific sequences
- after sequences are cut, they are run with gel electrophoresis to determine if mutations have removed restriction sequences
Real-Time PCR
- method used for molecular genetic diagnosis
- DNA amplification and detection steps occur simultaneously, allowing quantificaiton of template
- fluorescent reporter binds to template DNA and emits light when it is removed by exonuclease in polymerase; emits light in direct proportion to the amount of the PCR produced
- flourescent reporter can be:
- non-specific fluorescent dyes that intercalate with dsDNA
- sequence-specific DNA probes that are labelled with fluorescent reporter which permits detection only after hybridization of the probe with its complementary sequence
Next-Generation Sequencing
- method used for molecular genetic diagnosis that uses high thoughput sequencing
- parallelizes sequencing process, producing thousands/ millions of sequences at once
- sequencce can be analyzed hundreds of times, then sequences are aligned in order next to a base sequence
- mutations, large and small, can be identified
- ex. can help diagnose Marfan’s
Comparative Genomic Hybridization Array
- ssDNA fragments from patient are hybridized with red fluorescent particle and reference DNA is hybridized with green fluorescent particle
- two DNA sequences are hybridized to a normal human template (compete for spots) and fluoresence is examined
- equal expression: yellow
- overexpression of sequence in patient: green
- underexpression of sequence in patient: red
- ex. can be used to diagnose trisomy 18
Single Nucleotide Polymorphism Array
- looks for sequencing containing specific polymorphisms
- can detect copy number variaiton and zygosity (genetic material missing from maternal or paternal alleles)
- ex. diagnose uniparental disomy (Angelman syndrome)
What is Gaucher’s syndrome and why does it occur later in life?
lysosomal storage disease; lack of neural involvement