Path 1- chapter 6 Flashcards
(144 cards)
0
Q
What are point mutations (missense)?
A
a nucleotide base is replaced by another (codes for alternative AA; beta globin: sickle cell disease; nonsense mutation replaces a nucleotide base by a stop codon)
1
Q
Many congenital disorders are _________. not all hereditary disorders are _________. not all congenital disorders are _________.
A
hereditary; congenital; hereditary
2
Q
What are frameshift mutations?
A
insertion/deletion of 1 or 2 nucleotides, alters “reading frame” (insertion, deletion, duplication)
3
Q
What is a trinucleotide repeat?
A
amplification of a sequence of 3 nucleotides (fragile x syndrome)
4
Q
What is Pleiotropy?
A
single mutation may have a variety of phenotypic effects
5
Q
What is Li-Fraumeni syndrome?
A
TP53: various CAs
6
Q
What is genetic heterogeneity?
A
multiple mutations may be expressed as the same trait
7
Q
What is an autosomal dominant disorder?
A
1 parent is affected; offspring have a 50% chance of manifesting
8
Q
in an autosomal dominant disorder which is more expressed, homozygous or heterozygous?
A
heterozygous is most common
9
Q
What are factors associated with autosomal dominant disorders?
A
reduced penetrance (have mutation, but are phenotypically normal) and variable expressivity (same mutation is expressed differently within different individuals)
10
Q
What are autosomal recessive disorders?
A
largest group of mendelian disorders (most commonly disrupts enzymes; offspring have 25% chance of expressing disease)
11
Q
in an autosomal recessive disorder which is more expressed, homozygous or heterozygous?
A
homozygous
12
Q
What are x-linked disorders?
A
Most commonly x-linked recessive; transmitted by heterozygous females transmit; affects male offspring
13
Q
affected males (x-linked) transmit to daughters what percent of the time?
A
~100% carriers
14
Q
What is Marfans syndrome?
A
autosomal dominant (fibrillin gene mutation); skeletal, ocular, cardiovascular (pleiotropy); 85% familial, 15% sporadic
15
Q
What is fibrillin?
A
structural proteins, from fibroblasts
16
Q
What are the key skeletal, ocular, and cardiovascular problems associated with marfans syndrome?
A
skeletal: long limbs, high-arched palate, joint hypermobility
ocular: bilateral lens subluxation (ectopia lentis)
cardiovascular: ruptured aorta (lethal), mitral valve prolapse (floppy valve syndrome)
17
Q
What are some signs of marfans syndrome?
A
Wrist sign: thumb/index fingers overlap Steinberg sign (thumb sign) Pes Planovalgus (flatfoot) Dolichocephaly (elongated face)
18
Q
What is Ehlers-Danlos syndrome?
A
this is a group of single gene disorders; autosomal dominant or recessive; defective collagen synthesis/structure; collagen lacks tensile strength; hyper-extensible skin, hyper-mobile ligaments; vulnerable to trauma; poor wound healing (vessel fragility)
19
Q
What is familial hypercholesterolemia?
A
most common mendelian disorder (1:500); autosomal dominant; mutation is LDL receptor (LDLR) gene; hepatocytes: 75% of LDLRs; can be heterozygous or homozygous
20
Q
Who is likely to get heterozygous familial hypercholesterolemia?
A
adulthood onset (xanthomas; increase LDLs 2-3x); premature atherosclerosis
21
Q
What are xanthomas?
A
cholesterol deposits on tendons
22
Q
Who is susceptible to homozygous familial hypercholesterolemia?
A
Childhood onset; LDLs increase 5x; xanthomas
23
Q
Which is more severe heterozygous or homozygous familial hypercholesterolemia?
A
homozygous: children; more severe/lethal
heterozygous: adults; less severe
24
What is cystic fibrosis?
autosomal recessive; CFTR gene; decrease chloride ion transport; salty kiss; variable features: mild to lethal; chronic pulmonary infections (most common cause of death); GI and exocrine (pancreatic insufficiency- 90%); pseudomonas aeruginosa (80% by age 18)
25
What happens with the male reproductive system in cystic fibrosis?
95% males have azoospermia and male infertility (absent vas deferens)
26
What happens with the sweat glands in cystic fibrosis?
reduced resorption of sodium chloride (salty)
27
What is phenylketonuria (PKU)?
seen in 1:10,000 infants; autosomal recessive, affects homozygotes; severe mental retardation: age 6 months; urine and sweat is musty or mousy odor; decrease pigmentation (skin and hair)
28
tyrosine is a precursor to _______
melanin
29
What is maternal PKU?
Teratogen (crosses placenta)
30
What is galactosemia?
autosomal recessive (1:60,000); mutated galactose-1-phosphate uridyltransferase (GALT); abnormal galactose metabolism; galactose-1-phosphate accumulates; Failure to thrive, 1st week after birth
31
What is lysosomal storage diseases (LSDs)?
autosomal recessive, inherited; lack of lysosomal enzymes; metabolites accumulate (stored); early onset: infants/children
32
What are the 5 types of LSDs?
Tay-sachs disease; Niemann-pick disease, type A and B; Niemann-pick disease, type C; Gaucher disease; mucopolysaccharidosis
33
What is Tay-Sachs disease?
inability to metabolize Gm2 gangliosides; mutated hexosaminidase A enzyme; mental retardation, blindness, motor weakness; normal at birth, weakness by 6 mo.; risks are ashkenazi jews
34
What is Niemann-Pick disease, type A and B?
Acid sphingomyelinase deficiency; accumulation of sphingomyelin; early onset: evident during infancy
35
What is the difference between type A and type B niemann-pick disease?
Type A: most severe, visceromegaly + neuro. damage (fatal by age 3)
Type B: visceromegaly, no neuronal damage (limited to hepatosplenomegaly
36
What is niemann-pick, type C?
more common than type A and B, combined; defective lipid transport (mutated NPC1 or NPC2); cholesterol and Gm1 and Gm2 gangliosides accumulate; childhood onset, ataxia, dystonia (spasm), dysarthria, psychomotor regression
37
What is Gaucher's disease?
glucocerebrosidase gene mutation (glucocerebrosides accumulate); enlarged phagocytes: "gaucher cells"; severe hepatosplenomegaly; 3 types
38
What are the differences between the three types of Gaucher's disease?
Type 1= MC (99%), less severe, ashkenazi jews
| Type 2-3= more severe, neuro. disturbances
39
What is mucopolysaccharidosis?
group of disorders; deficiency in ECM breakdown enzymes; hepatosplenomegaly, clouding in cornea, course facial features, mucopolysaccharides in urine
40
What are the types of mucopolysaccharidosis?
Hurlers syndrome (type 1) and Hunter syndrome (type 2); both accumulate heparin sulfate and dermatan sulfate
41
What is Hurler syndrome (mucopolysaccharidosis)?
autosomal recessive, alpha-l-iduronidase deficiency; corneal clouding
42
What is Hunters syndrome (mucopolysaccharidosis)?
x-linked; L-iduronate sulfatase deficiency
43
What are glycogen storage diseases?
AKA glycogenoses; group of enzymatic deficiencies; inherited (most commonly autosomal recessive; glycogen accumulates (liver, skeletal muscles, heart
44
What are the types of glycogen storage diseases?
von Gierke disease (hepatic type); McArdle disease (myopathic type); Pompe disease (type II glycogenosis)
45
What is von Gierke disease (hepatic type)?
glucose-6-phosphatase deficiency; impaired liver glycolysis to hepatomegaly and hypoglycemia; failure to thrive
46
What is McArdle disease (myopathic type)?
muscle phosphorylase deficiency; impaired muscle glycolysis to weakness/cramps
47
What is pompe disease (type II glycogenosis)?
lysosomal acid maltase deficiency; every organ, cardiomegaly; lethal by age 2
48
What are complex multigenic disorders?
greater than 2 genes (small effect); environment "unmasks" the genetic trail; type 2 diabetes: obesity + genetic risks
49
What are features of complex multigenic disorders?
increase number of inherited genes = increased risk; identical twins share risk, decrease with non-identical; first degree relative have similar risk; expression in 1 offspring, increase risk in siblings
50
What are cytogenetic disorders?
altered chromosomes have a large influence on bodily structure and function; 50% of 1st trimester spontaneous abortions (1:200 live births); 23 chromosomes (haploid, n)
51
What are cytogenetic disorder abnormalities?
numeric (monosomy 2n-1; aneuploid, trisomy, 2n+1); structural (breaks, deletions)
52
What is polyploid?
3n, 4n
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What is a translocation?
transfer of a part of 1 chromosome to another chromosome
54
What is isochromosomes?
centromere divides horizontally, not vertically
55
What is robertsonian translocation?
centric fusion, chromosome lost
56
What are deletions?
loss of a portion of a chromosome
57
What are inversions?
2 interstitial breaks in a chromosome and the segment reunites after a complete turnaround
58
What is a ring chromosome?
a variant of a deletion after loss of segments from each end of a chromosome, arms unite to form a ring
59
Loss of genetic material is ______ severe
more (lethal)
60
Gain of genetic material is ______ severe
less
61
What are some examples of a gain in genetic material?
entire chromosome is a trisomy; part of a chromosome is robertsonian translocation
62
cyogenetic disorders most commonly result from __________ alterations
spontaneous (de novo changes)
63
What is an allosome?
sex chromosome; less severe, subtle phenotypic changes, infertility
64
What is trisomy 21?
Down syndrome; body and brain (1:700); most common
65
What is trisomy 13?
patau syndrome; cardiac and renal 1:15,000; microcephaly, lethal by age 1 (80%)
66
What is Cri du chat syndrome?
cat like cry; fragmented 5th chromosome, 1:50,000; cognitive and motor dysfunction, drooling
67
What is Down syndrome?
trisomy 21; most common chromosomal disorder (1:700); 95%: meiotic nondisjunction; 47 chromosome; increase maternal age; most common cause of severe mental retardation; cardiac malformations (40%); leukemia (20x)
68
Up to 30% of people with Down syndrome have ____ ______ instability
atlanto-axial
69
What is familial Down syndrome?
4% of cases; robertsonian translocation
70
What is 22q11.2 deletion syndrome?
deletion of hand 11 on chromosome 22
71
What are the two types of deletion syndromes?
DiGeorge syndrome and velocardiofacial syndrome
72
What is DiGeorge syndrome?
Thymic hypoplasia: decrease T cell immunity (increase infections); parathyroid hypoplsia: hypocalcemia (tetany)
73
What is velocardiofacial syndrome?
structural defects: cardiac, facial; mild immunodeficiency
74
What are allosomal cytogenetic disorders?
allosome= sex chromosome (n23); more compatible with life; relatively minor
75
What is the relatively minor allosomal cytogenetic disorders?
lyonization (x-inactivation: 1 female X chromosomes is inactivated, Barr body); very little info on y
76
What are hallmark conditions for allosomal cytogenetic disorders?
Klinefelter syndrome; Turner syndrome
77
What is Klinefelter syndrome?
greater than 2 chromosomes, greater than 1 Y (nondisjunction during meiosis); most common cause of male hypogonadism and sterility; 1:1,000 male births; gynecomastia (breast CA, increase 20x); risk is increased maternal age
78
What are Turners syndrome?
most common from an absence of 1 X chromosome (45,x); loss of short (p) arm of X (partial or complete); short stature, amenorrhea (streak ovaries), neck webbing, androgynous female appearance; cubitus valgus
79
What are single gene disorders with atypical inheritance?
don't follow mendelian patterns; hallmark examples: triplet-repeat mutations, mutations in mitochondrial genes, genomic imprinting
80
What are triplet repeat mutations?
AKA: trinucleotide repeat disorders; subset of microsatellite repeats, neurodegeneration
81
What are mutations in mitochondrial genes?
enzymes for oxidative phosphorylation
82
What is genomic imprinting?
epigenetic silencing of genes
83
What is fragile x syndrome?
triple-repeat mutation (FMR1 mutation); x-linked, primarily affects males; familial mental retardation; macroorchidism (90%); 30-50% female carriers develop fragile x; grandpa to carrier daughter to grandson
84
what is genetic anticipation?
features become more aggressive with each generation
85
What are the ratios for fragile x syndrome for men and women?
males: 1:1,550; females: 1:8,000
86
diseases caused by mutations in mitochondrial genes?
Rare; mitochondrial genes: strict maternal inheritance; hallmark: leber hereditary optic neuropathy; degeneration of retinal ganglia and CN II; loss of central vision, bilateral, progressive
87
What are the types of genomic imprinting diseases?
Angelman syndrome and Prader-Willi syndrome
88
What is angelman syndrome?
paternal imprinting and maternal deletion of 15q12 (laughter; "happy puppet syndrome")
89
What is a Prader-Willi syndrome?
maternal imprinting and paternal deletion of 15q12; obesity (hyperphagia)
90
What are pediatric diseases?
pediatric: birth through age 17 years; infant, child, adolescent
91
What are infant pediatric diseases?
birth through 1st year (neonate: birth through 4 weeks- highest risk)
92
What are child pediatric diseases?
birth to puberty
93
What are adolescent pediatric diseases?
puberty to adulthood
94
What are congenital disorders?
3% of neonates: illness, disability, death (features: cosmetic to lethal)
95
What is the leading cause of death in infants?
congenital malformations, chromosomal abnormality
96
What is the leading cause of death for 1-14 years?
accidents
97
What are features of congenital disorders?
polydactyly, cleft lip, tetralogy of fallot; stillbirth
98
What are transcervical perinatal infections?
ascending; from vagina to cervix; most common is bacterial (strep)
99
What are transplacental perinatal infections?
hematogenous (blood) spread; crosses placenta (mc) or transfusion at birth; TORCH infections
100
What are the TORCH infections?
T: toxoplasma; O: other (treponema pallidum, HIV, HBV, TB, plasmodium falciparum); R: rubella virus; C: CMV; H: HSV
101
What is prematurity restrictions?
less than 37 weeks gestations, 2nd MC cause of neonatal mortality (number 1 congenital defects)
102
What are the small-for-gestational-age growth restrictions?
chromosomal disorders, fetal infection, placental factors, various maternal factors (MC)
103
What are the terms of pregnancy?
pre-term: <37 weeks; early term: 37-38 weeks; full term: 39-40 weeks; late term: 41st week; post-term: ≥ 42 weeks
104
What is respiratory distress syndrome?
immature lungs: decrease surfactant production; difficulty inflating alveoli (atelectasis); hyaline membrane disease; surfactant: type II pneumocytes, 1st breath
105
What is necrotizing enterocolitis?
prematurity, enteral feeding (feeding tube); most common location, ileum, cecum, ascending colon; bloody stool to distention to circulatory collapse
106
What is Sudden infant death syndrome?
most common 2-4 months; during sleep; 3rd most common cause of death during infancy; most common after first month
107
What is the SIDS triple risk model?
vulnerable infant; critical developmental period for homeostatic control (1 month-1 year); decrease arousal or cardiorespiratory control
108
What is fetal hydrops?
accumulation of edema, during gestation; stillborn, die within first few days after birth, complete recovery
109
What is hydrops fetalis?
generalized edema, lethal
110
What is cystic hygroma?
local edema, may not be lethal
111
What are immune hydrops?
antibody induced hemolysis (incompatibility, rare to due Rh antibody prophylaxis)
112
What is nonimmune hydrops?
most common; chromosomal abnormalities (45X; trisomies), cardiovascular defects
113
What are pediatric tumors?
Cancer; 2nd most common cause of death from 4-14 years; 3 benign pediatric tumors
114
What are the 3 types of benign pediatric tumors?
hemangioma, lymphangioma, and sacrococcygeal teratomas
115
What is a hemangioma?
most common tumors of infancy; endothelial capillary tumor; infancy, self-resolves by age 7 years
116
What are lymphangiomas?
lymphatic counterpart of hemangiomas; most common at neck, trunk, axilla
117
What are sacrococcygeal teratomas?
most common germ cell tumors of childhood; 75% benign, ≤4 months old, MC external; 12% malignant, older children, lethal; 13% are "immature teratomas," increase anaplasia= increase malignant potential
118
What are pediatric malignant tumors?
differ from adult CA; teratogens, genetic abnormalities; spontaneously regress; more favorable prognosis
119
What are 3 unique pediatric cancers?
neuroblastoma, retinoblastoma, wilms tumor
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What is a neuroblastoma?
malignant tumor, 98% sporadic
121
Infantile malignancy is ______ neuroblastoma
50% (7-10% of pediatric CA)
122
Neuroblastomas have homer-wright pseudo-rosettes. what are they?
neutrophils surrounded by tumor cells (90% secrete catecholamines)
123
Which age group has a better prognosis for neuroblastoma?
younger (<18 months) have better prognosis
124
What are features of neuroblastoma for children <2 years?
protuberant abdomen (tumor and edema), fever, cachexia, mets to skin ("blueberry muffin baby")
125
What are features of neuroblastomas for children >2 years?
may go unnoticed, until signs of metastasis; hepatomegaly, osseous pain, ascites (fluid in peritoneal cavity)
126
Neuroblastomas metastasize via _________ and __________ systems
lymphoid and hematopoietic (liver, lungs, bone marrow); spontaneous resolution is common
127
Retinoblastoma is malignant and is the MC _______ ___ malignancy
pediatric eye (post. retina)
128
Retinoblastoma can be genetic or sporadic. Which is more common?
Sporatic (60%): sporadic RB1 mutation; isolated and unilateral tumors
(genetic 40%: inherited RB1 mutation; MC multiple bilateral tumors; Risk: osteosarcoma, other soft tissue tumors
129
Retinoblastoma incidence ______ with age (MC age __ years)
decreases; 2
130
What are unique characteristics for retinoblastoma?
may be congenital; risk of other primary tumors (RB mutation, TSG); may spontaneously regress
131
the nodular mass for retinoblastomas is on the ____ retina
posterior
132
Retinoblastoma mets to _______ _____, via optic nerve
subarachnoid space (METS: CNS, calvarium, peripheral osseous structures, lymphatic system)
133
Retinoblastomas have flexner-wintersteiner rossettes. What are they?
cuboidal cells surrounding empty lumen
134
Retinoblastomas has a characteristic called the ____ ____ reflex
cat eye
135
What is wilms tumor (nephroblastoma)?
malignant; MC pediatric kidney tumor, 2-5 years old
136
Wilms tumor is an enormous tumor + other congenital malformations. What are some symptoms of wilms?
abdominal pain, fever, hematuria; palpable mass
137
What is WAGR syndrome? (wilms tumor)
W= wilms; A= aniridia, G= genitourinary, R= mental retardation
138
What are other syndromes associated with wilms tumor?
denys-drash-syndrome (DDS) and beckwith wiedemann syndrome
139
Does wilms tumor have a good or bad prognosis?
good prognosis (treatment with nephrectomy and chemotherapy)
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What are prenatal indications for genetic analysis?
any increase risk of chromosomal abnormality; maternal age >34 years, chromosomal abnormality in previous child, carrier of x-linked condition; amniocentesis, umbilical cord blood, or biopsy
141
What are postnatal indications for genetic analysis?
congenital anomalies, mental retardation, developmental delay, history of multiple spontaneous abortions, infertile offspring; peripheral blood lymphocytes
142
What are congenital disorders?
present at birth (not always inherited)
143
What are hereditary disorders?
inherited in germ line; transmitted to offspring; genetic, familial
