1
Q
What % of spontaneous abortions during early gestation (1st trimester) have a chromosomal abnormality?
A
50%
2
Q
What is a mutation?
A
Permanent change in DNA
3
Q
What are genome mutations?
A
Loss or gain of whole chromosomes
4
Q
What are gene mutations?
A
Gives rise to visible structural changes in the chromosomes
5
Q
What are the diff kinds of point mutations within a coding sequence?
A
- Missense (alter meaning of code)
- Nonsense (stop codon)
- Frameshift (3 codons -> catastrophic results)
- Silent
- Nonsense + frameshift are the most destructive
6
Q
What are tri-nucleotide (3 codons) repeat mutations?
A
- When you have too many copies of a certain nucleotide triplet (caused by an increased # of CAG repeats)
- Fragile X: involved gene is FMR-1
- 2nd most common cause of genetic mental retardation (Down Syndrome = 1st)
- Marco-orchidism (large testes), large everted ears, autism, MVP = symptoms
- Huntington’s disease
- Myotonic dystrophy
- Friedreich’s ataxia
- Usually cause neurological disorders
7
Q
What is imprinting?
A
At a single locus (area) only 1 allele is active, the other is inactive (imprinted/inactivated by methylation)
- Only one working copy is inherited w/ imprinting
- Deletion of the active allele -> disease
8
Q
What are 2 disease from imprinting?
A
- Prader-Willi syndrome
- Deletion of normally active paternal allele
- Mental retardation, hyperphagia, obesity, hypo-gonadim, hypotonia
- Angelman’s syndrome
- Deletion of normally active maternal allele
- Mental retardation, seizures, ataxia, inappropriate laugher (“happy puppet”)
9
Q
Explain the percentages in a punnet square
A
AA = dominant gene = 25%
Aa = carriers (heterozygous) = 50%
aa = homozygous carriers (recessive) = 25%
- percentages stay the same for every child
10
Q
What is variable penetrance?
A
Even heterozygous can show some disease
11
Q
What are the 5 modes of inheritance?
A
- Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant
- Mitochondrial inheritance
12
Q
How can you tell from a family pedigree that a disease is autosomal dominant? Autosomal recessive?
A
- Dominant = see the disease in every generation
- Recessive = skips generations
- Every line in the tree represents a generation
13
Q
What are characteristics of autosomal (non-sex) dominant disorders?
A
Changes to non-enzymatic proteins involved in regulation of complex metabolic pathways that are subject to feedback inhibition
- Seen in every generation
- Females + Males affected
- Only need 1 copy of gene to have disorder/trait
- Often pleotropic (1 gene has more than 1 effect on individual’s phenotype)
- Presents clinically after puberty
14
Q
A parent with an autosomal dominant disorder has what % chance of giving it to their offspring (for each pregnancy)?
A
50%
15
Q
What is the mnemonic for Autosomal Dominant disorders?
A
Very Powerful DOMINANT Humans
16
Q
What are characteristics of autosomal (non-sex) recessive disorders?
A
Change in enzymatic proteins (often loss of fx)
- Can skip generations, due to carrier state
- Parents often present in childhood
- You need 2 copies of gene to have trait or disease
17
Q
What are some autosomal recessive disorders?
A
- Tay-Sachs
- Albinism
- ARPKD
- Cystic fibrosis
- Sickle cell anemia
- Glycogen storage diseases
- Hemochromatosis
- Mucopolysaccharidoses (except Hunter’s)
- Phenylketonuria (PKU)
- Sphingolipidoses (except Fabry’s)
- Thalessemias
18
Q
What is Cystic Fibrosis?
A
Defect in CFTR gene -> affects cAMP pathway -> Cl- channel disorder -> affects mostly lungs, also pancrease, liver, kidneys, intestine
- More viscous mucous -> difficulty breathing/frequent lung infx
- 1/3200 live births
- Most common lethal genetic disease in caucasians (N. Euros)
- No known cure
- Autosomal recessive
19
Q
What is the 1st sign of cystic fibrosis?
A
Bowel obstruction due to meconium ileus (while baby eats in belly, meconium is the 1st poop of baby’s bowel - it can get thick and cause obstruction)
20
Q
What does cystic fibrosis lead to?
A
- Mucous plugging/infx (pseudomonas)
- Pancreatic insufficiency
- Increased sodium chloride in sweat (Cl sweat test)
- Can develop infertility
21
Q
What is sickle-cell anemia?
A
Hereditary, multi-sx disorder who cardinal features are hemolytic anemia + recurrent pain
- Chronic hemolytic disease
- Primarily in african-amer pop
- Mis-shaped, sickled RBCs become trapped in small capillaries/block circulation -> vaso-occlusive crises -> extreme pain in chest/bones/abdomen
- Autosomal recessive
22
Q
What is sickle cell disease vs sickle cell trait?
A
- Disease = homozygous (both copies of mutated beta gene)
- Trait = heterozygous (1 copy of mutated gene)
- 10% african-amer have sickle cell trait
23
Q
What is phenylketonuria (PKU)?
A
Inborn error of metabolism (enzymatic mutation)
- No phenylalanine hydroxylase -> can’t convert to tyrosine
- Must avoid phenylalanine in diet (which is in all foods containing protein)
- 1/12,000 caucasians
- Autosomal recessive
- Affects brain development (increase chance of seizures, mental retardation, autism)
24
Q
What are clinical features of PKU?
A
- Initially healthy newborns
- Few weeks develop brain impairement
- 6 mos severe mental retardation
- Seizures, decreased pigmentation of hair/skin
- “Mousy” or musty odor in breath, skin, or urine
25
What is **galactosemia**?
Inborn error of galactose metabolism (enzymatic mutation)
* Lacking galactose-1-phosphate uridyltransferase
* 1/60,000
* **Autosomal recessive**
26
What are clinical features of galactosemia?
* Born normal then fail to thrive
* Liver - jaundice, liver damage
* Ocular - cataracts
* GI - vomiting, diarrhea
* E. coli sepsis
* Neurologic impairement
27
What do lysosomes contain?
Hydrolytic enzymes necessary for intracellular digestion
28
What are **sphingolipidosis**?
Storage diseases characterized by abnormal storage of sphingolipids
29
What are **lysosomal storage diseases**?
* 40 lysosomal storage disorders
* **Autosomal recessive**
* Infants and young children
* Cellular dysfunction
* Hepatosplenomegaly
* CNS involved
30
What is **Tay Sachs**?
* Lysosomal storage disease (type of gangliosidoses)
* Gm2 gangliosides
* Lack of lysosomal hexosaminidase A
* CNS
* **Autosomal recessive**
* Chromosome 15
* Common is Ashkenazi Jews (Carriers 1/30)
31
What are clinical features of Tay Sachs?
* **Neurodegenerative**
* Motor weakness by 3-6 months of age
* Severe mental retardation
* Blindness
* **Cherry red spot in eyes**
* Death usually by 4-5 yrs
32
What is **Niemann-Pick Disease**?
Inability to metabolize sphingomyelin (lacking sphingmyelinase)
* Accumulation of lipid in phagocytic cells/neurons
* **Autosomal recessive**
* Lysosomal storage disease
33
What are clinical features of Niemann-Pick disease?
* Spleno + hepatomegaly
* Affects lungs, bone marrow and lymph nodes
* Neuronal damage -\> severe neurologic deterioration
34
What are the 4 different types of Niemann-Pick disease?
* Type A = infants, death within 3 years of life (worst)
* Type B = pre-teen yrs, no neuro involvement (able to live w/)
* Type C + D = mix of both, difficulty in walking/swallowing, progressive loss of vision/hearing
35
What is **Gaucher disease**?
* Most common lysosomal storage disease
* Inability to metabolize glucosylceramide (no glucocerebrosidase)
* **Autosomal recessive**
* Ashkenazi Jews (carrier 1/12)
* Affects phagocytes + accumulates in liver, spleen, bone marrow + less commonly brain
36
What are the clinical features of Gaucher disease?
* Pancytopenia, splenomegaly, osteopenia, bone lesions, bone pain
* Anemia, low platelets, bruise easily
* Tx: enzyme replacement therapy and bone marrow transplantation
37
What are the different types of Gaucher disease?
* Type 1: No brain involvement, splenohepatomegaly, skeletal disorders
* Type 2: 3 mos old - brain damage, death by 2 yrs
* Type 3: Infantile type, splenohepatomegaly variable, brain involvement (seizures)
38
What are **x-linked recessive** disorders?
* Males are hemizygous (1 copy present)
* Females have 2 X's, males have 1 X (very rarely affects woman)
* All daughters are carriers
* Heterozygous females express disorder partially (variable penetrance b/c of 1 X)
* NO male-to-male transmission
39
What are exs of X-linked recessive disorders?
* Brutons' agammaglobulinemia
* Wiskott-Aldrich syndrome
* Fabyr's disease
* G6PD deficiency
* Ocular albinism
* Lesch-Nyhan syndrome
* Duchene and Becker's muscular dystrophy
* Hunter's syndrome
* Hemophilia A and B
40
What is **G6PD** deficiency?
* X-linked recessive
* Most individuals asymptomatic
* Symptomatic pts usually male
* ~400 known mutations in the gene coding for G6PD
* Prolonged neonatal jaundice seen in a newborn
* Hemolytic crisis in response to:
* Ilness
* Certain drugs, food **(fava beans)**, chemicals
* Diabetic ketoacidosis
41
What are **X-linked Dominant** disorders?
* Only given through X gene and not Y
* Usually affects males worse b/c only have 1 X gene
* Rare!!
* Transmitted through both parents
* ex: **Vitamin D-resistant rickets**
42
What are **mitochondrial diseases**?
A group of genetic disorders that are caused by dysfunctional mitochondria (maternal inheritance)
* Unique characteristics b/c mito = critical to cell fx
* **Mitochondrial myopathy** = subclass that has neuromuscular disease sx
* Sx are worse when diseased mito present in muscles, cerebrum or nerves
* Sx: poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilites, heart disease, liver disease, kidney disease, GI disorders, respiratory disorders, neurological problems, autonomic dysfunction, dementia
43
What are **Autosomal Trisomies**?
* Down Syndrome: Trisomy **21**
* Edwards' Syndrome: Trisomy **18**
* Patau's Syndrome: Trisomy **13**
44
What is **Trisomy 21**?
Down Syndrome (chromosomal/cytogenic disease)
* Most common
* 47 chromosomes
* **Aneuploidy**: meiotic non-disjunction (when chromosomes do not separate -\> have 3 of those chromosomes - 2 from 1 parent + 1 from other)
* Other type: mosaicism, unbalanced translocation (uncommon)
45
What is associated w/ higher risk of down syndrome?
Maternal age
* 1/1550 live births -\> under 20 yrs
* 1/25 -\> older than 45 yrs
46
What are clinical features of Down syndrome?
* Epicanthic fold (above the lip)
* Flat facial profile
* Simian crease
* Tongue protrusion
* A degree of mental retardation (varies)
* Congenital malformations: cardiovascular + GI/GU
47
What is mosaicism?
Accounts for about 1% of down syndrome cases
* Nondisjunction of chromosome 21 takes place in 1 (but not all) of initial cell divisions after fertilization -\> mixture of 2 types of cells (some containing usual 46 chromosomes, and others 47)
* Cells w/ 47 chromsomes contain an extra chromosome 21
48
What is translocation?
4% of all cases of Down's
* Part of chrom 21 breaks off during cell divison + attaches to other chromosome (typically chrom 14)
* Total # of chrom remain 46, presence of an extra part of chrom 21 causes characteristics of Down's
49
What is **Trisomy 18**?
Edward's syndrome
* Types: mosaiciam + translocations
* 1/3,000 live births, w/ a maternal age effect
* Most fetuses are miscarried before term OR baby is stillborn
* Diseases affecting the larger chromosomes have potential to be more catastrophic
* 80% female
* 30% die within a month of birth
* 10% beyond 1 year, w/ profound learning disabilities
50
What are clinical features of Edward Syndrome?
* Clenched hands w/ overlapping fingers
* Crossed legs
* Rocker-bottom feet
* Low birth weight
* Low-set ears
* 10-20% risk of acute leukemia
* Mental deficiency
* Microcephaly
* Micrognathia (small tongue)
* Congenital abnormalities of heart/kidneys
51
What is Trisomy 13?
Patau syndrome
* Chromosome 13 presents 3 times instead of 2
* 4% w/ unknown outcomes are likely to result in a live birth
52
What is **Klinefelter Syndrome**?
Affects male patients 47, XXY (they have more than one X)
* XXXY, XXXXY
* 1:1000
* Most common cause of hypogonadism in males
* Non-disjunction, mosaicism
* The more X's, the more severe
53
What are clinical features of Klinefelter Syndrome?
* Tallness w/ extra long arms and legs, short trunk
* Gynecomastia (man boobs)
* Lack of facial/body hair
* Hypogonadism and small penis
* Infertility
* Social/learning disabilities
* Normal -\> borderline IQ
54
What is **Turners Syndrome**?
45, X
* Monosomy of the X chromosome
* Affects only **females** (will only have one X chromosome instead of 2)
55
What are clinical features of Turners?
* Short stature
* Web neck
* Low hairline
* Cubus Valgus
* Shield chest
* Primary amenorrhea...streak ovaries (ovaries aren't working -\> will not menstruate)
* Coarctation of aorta (aorta dividing into 2)
56
Marfan Disease, Ehlers-Danlos syndrome, and Osteogenesis Imperfecta are all defects in?
Structural proteins
57
What is **Marfan's Syndrome**?
Fibrillin gene mutation, affects skeleton/heart/eyes
* Tall w/ long extremities, pectus carinatum, hyper-extensive joints, long fingers/toes (**arachnodactyly**), subluxation of lenses
* Cystic medial necrosis of aorta -\> incompetence + dissecting aortic aneurysm
58
What is **Ehlers-Danlos Syndrome**?
Faulty collagen synthesis -\> hyperextensive skin, tendency to bleed, hypermobile joints
* Inheritance/severity varies
* Can develop berry aneurysm or organ rupture
59
What is **Osteogenesis Imperfecta**?
Genetic brittle bone disease
* Most common form is **autosomal dominant (AD)** w/ abnormal **Type 1** collagen
* Multiple **fxs** w/ minimal trauma due to brittle bones
* **Blue sclerae** due to translucency of CT over choroid
* Hearing loss
* Lack of dentin (dental imperfections)
60
What is **familial hypercholesterolemia**?
Defect in receptor protein (mutation in gene encoding LCL receptor)
* Loss of feedback control -\> elevated cholesterol
* **Heterozygotes**: 2-3x elevation in plasma cholesterol
* Tendinous xanthomas + premature atherosclerosis
* **Homozygotes**: 5-6x elevation in plasma cholesterol
* SKin xanthomas, cerebral/peripheral atherosclerosis at early age
* Can have MI before age of 20
* Tx: statins (inhibit HMG CoA reductase -\> greater synthesis of LDL receptors)
61
What is a **Robertsonian Translocation**?
Non-reciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22
* Occurs **when long arms of 2 acrocentric chromosomes** (chromosomes w/ centromeres near their ends) **fuse at the centromere and the 2 short arms are lost**
* Balanced translocations -\> no abnormal phenotype (normally)
* **Unbalanced translocations** -\> miscarriage, stillbirth, chromosomal imbalance (Down's, Patau's, etc.)
62
What are 3 syndromes caused by **micro-deletions**?
1. Cri-du-chat syndrome
2. Williams syndrome
3. 22q11 deletion syndrome
63
What is **Cri-du-chat syndrome**?
Deletion of short arm of chromosome **5**
* Findings: micro-cephaly, moderate -\> severe mental retardation, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities
64
What is **Williams Syndrome**?
Deletion of long arm of chromosome **7**
* Findings: distinctive "elfin" facies, mental retardation, hypercalcemia, well-developed verbal skills, extreme friendliness w/ strangers, cardiovascular problems
65
What are 22q11 deletion syndromes?
* **DiGeorge syndrome** - thymic, parathroid and cardiac defects
* **Velocardiofacial syndrome** - palate, facial/cardiac defects
66
Are Y-linked dominant disorders as severe as X-linked dominant disorders?
Not as severe b/c Y chromosome only contains a few genes
* ex: color blindness
67
What is the diff between codominance and incomplete dominance?
* Codominance = both alleles show their effect and DO NOT BLEND (both parents have dominant alleles)
* Incomplete dominance = both alleles blend their effects
Pathology Exam 1
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