Chapter 5 Flashcards
(269 cards)
1
Q
What percentage of spontaneous abortions have chromosomal abnormalities
A
50%
2
Q
What percentage of newborns contain a gross chromosomal abnormality
A
1%
3
Q
Will mutations in somatic cells cause defects in progeny
A
No
4
Q
What is a single base nucleotide substitution
A
The base is changes, potentially resulting in the change of a single amino acid
5
Q
What is a missense mutation
A
Single base mutation resulting in the change of amino acid
6
Q
What is conservative amino acid base substitution
A
The change in amino acid is so similar, that the function of the protein causes little change
7
Q
What is the amino acid sequence change that results in Beta-globin chain sickle cell anemia
A
CTC (GAG in mRNA) which is a glutamate —> CAC (GUG in mRNA) which is a valine
8
Q
What is a nonsense mutation
A
The base change results in a stop codon
9
Q
What is B0-thalassemia
A
Beta-globin chain is prematurely stoped due to nonsense mutation, resulting in immediate degradation
10
Q
In the Beta-0 globin allele, what amino acid die the change occur and what amino acid stops
A
38 is the amino acid change and stops there resulting from a change to a stop codon
11
Q
What is a frameshift mutation
A
Change in amino acid number (addition or deletion) of a nonmultiple of 3
12
Q
What is the usual result of a frameshift mutation
A
Variable number of incorrect amino acids followed by a premature stop codon
13
Q
Which bases do almost all trinucleotide repeats incorporate
A
Cytosine and Guanine
14
Q
What type of mutation results in taysachs disease
A
Frameshift mutation (addition of 4 amino acids)
15
Q
What type of mutation results in the blood allele Group O
A
Frameshift mutation from the addition of a single nucleotide
16
Q
What are the conditions that are incorporated into single gene disorders with nonclassical patterns of inheritance
A
1) Triple-repeat mutations
2) mutations in mitochondrial DNA (mtDNA)
3) genomic imprinting and gonadal mosaicism
17
Q
What does the term congenital mean
A
Means born with, but does not have to be familial (ex congenital syphilis)
18
Q
What are virtually all Mendelian disorders
A
Mutations in single genes that have large effects
19
Q
What percentage of non expressive recessive mutations arefamilial
A
80-85%
20
Q
Sickle cell anemia is caused by what
A
Substitution of normal hemoblobin (HbA) with hemoglobin S (HbS)
21
Q
Under which conditions with a heterozygous individual for sickle cell express the RBC sickling (aka sickle cell trait)
A
Under lower oxygen tension
22
Q
What are two examples of codominance
A
Blood group compatibility and MHC
23
Q
What is pleiotropism
A
A single gene mutant leads to many effects
24
Q
What is genetic heterogeneity
A
Mutations at several genetic can produce the same trait
25
Sickle cell mutation is described as what
Pleiotropism
26
How is sickle cell an example of pleiotropism
The disfigured sickle cells can log jam vessels, leading to splenic fibrosis, organ infarcts, and bone changes
27
Mutations involving a single gene follow which of three patterns
1) Autosomal dominant
2) Autosomal recessive
3) X-linked
28
How is it possible to have an autosomal dominant gene expressed in a chid but not in a parent
There is a new mutation in either the sperm of the egg they were derived from
29
In the case of a child who inherited an autosomal dominant trait from unsympotomatic patients, how likely are subsequent siblings to develop the disease
Not at all, as siblings are not effected not at higher risk
30
If a disease causes a decrease in reproductivity, how is the trait passed on
Usually a result of a new mutation. Commonly seen in germ cells of older father
31
What is incomplete penetrance
Inheriting the mutant gene, but phenotypically normal
32
Neurofibromatosis type 1 presents what type of expressivity
Variable expressivity
33
What is the result of loss of 50% of LDL receptors
Secondary elevation of cholesterol that predisposes pt to atherosclerosis
34
What is dominant negative
In genes that are autosomal dominant, the loss of one gene impacts the functionality of the working gene such that there is no viable product
35
How is collagen an example of dominant negative
Collagen is a trimeric structure. Loss of function on one of the strands leads to the inability to form the whole structure
36
Transmission of a disorder produced by a gain of function mutation is almost always what
Autosomal dominant
37
How is Huntington disease an example of gain of function disease
Mutation gives rise to abnormal protein called Huntington, which is toxic to neurons, so even a heterozygote can develop disease
38
What type of disorder makes up the largest category of disorders
Autosomal recessive
39
Almost all inborn errors of metabolism are what kind of disorder
Autosomal recessive
40
What are the characteristic findings of autosomal recessive that separate them from other disorders
- Complete penetrance
- onset early in life
- more uniform expression
- New mutations are rarely seen clinically
- Many of the genes encode enzymes
41
Why is the there no Y linked inheritance
Because disorders on Y chromosome usually lead to infertile males
42
Males are considered what with regards to X chromosome
Hemizygous for X linked mutant genes
43
What is the rate of inheritance of a positive X linked disorder male
Will not pass to male sons, all daughters are carriers
44
How is a heterozygous female able to express phenotypically the X linked disorder
Random inactivation of an X chromome could cause the normal X to be silenced
45
What is the heritability of G6PD deficiency
X linked
46
How does G6PD deficiency affect females who are heterozygous
X linked trait, so affects males via hemolysis. Females will have some RBCs that are enzyme deficient and can still result in hemolysis
47
What is the heritability pattern of an X linked dominant disorder from the father
Gives to all of the daughters, and none of the sons
48
What is the example of X llinker dominant disorders
Vitamin D resistant rickets
49
What is type of heritability disorder for Huntington disease
Autosomal dominant
50
What is type of heritability disorder for Neurofibromatosis
Autosomal dominant
51
What is type of heritability disorder for Myotonic dystrophy
Autosomal dominant
52
What is type of heritability disorder for Tuberous sclerosis
Autosomal dominant
53
What is type of heritability disorder for Polycystic kidney disease
Autosomal dominant
54
What is the result from a mutation resulting in the decreased synthesis of an enzyme with reduced activity or reduced amount of normal enzyme
Metabolic block
55
The mutation in galactose-1 phosphate uridyltransferase results in the buildup of which product
Galactose
56
What is the result in the defect in tyrosinase
Deficiency in melanin, leading to albinism
57
What is the result of the metabolic block in alpha1-antitrypsin deficiency
Failure to inactivate neutrophil elastase in lungs
58
What is the result of a mutated LDL receptor in familial hypercholesterolemia
Reduced synthesis of LDL, decreased transport of LDL into cell, increased cholesterol in blood, increased cholesterol synthesis
59
What is the general characteristics of thalassemias
Mutations in globulin genes that result in a decrease in the amount of globulin chains made
60
What drug is contraindicated in G6PD deficiency
Primaquine
61
What is the result of administration of antimalarial drug primaquine to a G6PD deficient patient
Hemolytic anemia
62
What the three systems mainly affected by Marian syndrome
Skeleton, eyes, and cardiovascular system
63
What is the prevalence of Marian syndrome
1 in 5000
64
What is the percentage of Marian syndrome cases that are familial and transmitted by autosomal dominant inheritance
70 to 85%
65
What does the pathogenesis of Marfan come from
Defect in extracellular glycoproteins called fibrillin 1
66
What are the two general mechanisms that Marfans syndrome results in weakened connective tissue
- Loss of structural support in micro fibril rich connective tissue
- Excessive TGF beta signaling
67
The fibrils that are affected in Marfans serve which purpose
Act as scaffolding for tropoelastin, which is deposited to from elastic fibers
68
What are the main locations of elasticity loss in Marfans
Aorta, ligaments, ciliary zonules (supporting the lens)
69
FBN1, which codes for fibrillin-1, is located on which chromosome location
15q21.1
70
FBN2, which codes for fibrillin-2, is located on which chromosome location
5q23.31
71
Mutations in which gene is the underlying mechanism of pathogenesis in Marfans
FBN1
72
What does a mutation in FBN2 cause
Congentical contractural arachnodactyly
73
What is congenital contractural arachnodactyly caused by and what is the pattern of inheritance
Autosomal dominant, mutation in FBN2
74
What is haploinsufficiency
Reduction of fibrillin content below threshold, resulting in connective tissue weakness
75
What is the correlation between TGFbeta levels and Marfans
Marfans has excessive TGFbeta due to loss of microfibrils. Increases MMP and the loss of ECM
76
What are the normal clinical features of a healthy patient with Marfans
-Tall, with long extremities, tapering fingers and toes. Double jointed with a hyperextended thumb. Frontal eminences and prominent supraorbital ridges.
77
What will a patient with Marfans present with regards to spinal deformities
Kyphosis, scoliosis, rotation or slipping of the lumbar vertebra
78
What will a patient with Marfan present with regards to the chest
Lecture excavatum is pigeon breasted
79
What will a patient with Marfan present with regards to ocular changes
Ectopia lentis, aka bilateral subluxation or dislocation of the lens
80
A patient presenting with ectopic lentis, or outward and upward dislocation of the lens should be checked for which condition
Marfans
81
What are the commonly seen CV findings in a pt with Marfans
Mitral valve prolapse, dilation of the ascending aorta (due to cystic medionecrosis)
82
What is the common cause of death in Marfans patients and what is the percentage
Aortic dissection/hemorrhage in 30-45% of pts
83
What is required for the diagnosis of Marfans
Major involvement of two organ systems (MSK, CV, Ocular, Skin) and minor involvement of another organ
84
What is the main treatment for Marfans
Beta blockers to decrease HR and aortic stress
85
Ehlers-Danlos Syndrome (EDS) is caused by which general underlying condition
Defect in the synthesis or structure of collagen
86
Which of Mendelian patterns does Ehlers-Danlos Syndrome (EDS) encompass
All 3 principles
87
What are the locations of structures most affected by Ehlers-Danlos Syndrome (EDS)
skin, ligaments and joints
88
What are the serious complications seen in patients with Ehlers-Danlos Syndrome (EDS)
-Rupture of colon and large arteries, cornea and retinal detachment, diaphragmatic herniation
89
What is the most common form of Ehlers-Danlos Syndrome (EDS)
Lyphoscoliosis type
90
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 1
Aka classic
| Autosomal dominant
91
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 2
Autosomal dominant
92
What is the herititability of Ehlers-Danlos Syndrome (EDS) type 3
Aka hypermobility’
Autosomal dominant
93
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 4
Aka vascular
Autosomal dominant
94
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 6
Aka hyphoscoliosis
Autosomal recessive
95
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7a/b
Aka arthrochlasias
Autosomal dominant
96
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7c
Aka dermatosparaxis
Autosomal recessive
97
What is the mutation coding in Ehlers-Danlos Syndrome (EDS) kyphoscoliosis
Lysyl hydroxylase (can not hydroxylate lysine residues)
98
What is the mutation code in Ehlers-Danlos Syndrome (EDS) vascular type
COL3A1, giving rise to abnormalities in collagen type 3
99
What is the defect in Ehlers-Danlos Syndrome (EDS) arthrochalasia type
COL1A1 and COLA1A2, which is defect in conversion from procollagen to collagen via defect in the pro-alpha chains (resist cleavage)
100
What is the defect in Ehlers-Danlos Syndrome (EDS) dermatosparaxis type
Mutations in procollagen-N-peptidase gene, preventing cleavage from procollagen to collagen
101
What is the defect in Ehlers-Danlos Syndrome (EDS) classic type
COL5A1 and COL5A2
102
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 1/2
Skin and joint hyper mobility, strophic scars, easy bruising
103
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 3
Joint hypermobility, pain, dislocations
104
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 4
Thin skin, arterial and uterine rupture, bruising, small joint hyperextendability
105
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 6
Hypotonia, joint laxity, congenital scoliosis, ocular fragility
106
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7a/b
Severe joint hyper mobility, skin changes, scoliosis, bruising
107
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7c
Severe skin fragility, cutis lata, bruising
108
What is the level of plasma cholesterol levels in homozygous individuals
5-6 times the normal
109
What percentage of the body’s cholesterol is in plasma and how is it circulating
7% of total, mostly in LDL
110
What is the steps of cholesterol synthesis
1) Secreted as VLDL by liver (rich in triglycerides)
2) Cleaved by lipoprotein lipase, forming IDL
3) IDL (enriched in cholesteryl esters) retains B-100 and E
4) IDL taken up by the liver or formed into LDL
111
What is the immediate and main source of LDL
IDL
112
What are the two fates of IDL
1) Taken up by liver to make more VLDL
| 2) Formed into cholesterol rich LDL
113
What is the receptor used for uptake of IDL and what is it recognizing
LDL receptor and recognized ApOE and Apo100
114
What is the major location of LDL clearance and what is the percentage
70% by the liver
115
In lysosomes, what are the lipoproteins and cholesteryl esters broken down into
Lipoprotein into free amino acids
| Cholesteryl esters into free cholesterol
116
What is the mechanism that free cholesterol enters the cytoplasm
Via NPC1 and NPC2, which transports them
117
What effect does cholesterol have on synthesis of cholesterol, and what is the mechanism
Inhibits synthesis by inhibiting activity of HMG-COA reductase
118
What effect does cholesterol have on the enzyme acyl-coenzyme A
Increases activity, which is A cholesterol acyltransferase (favors esterification and storage of excess cholesterol)
119
What affect does cholesterol have on LDL receptor production
Inhibits (protection from excessive cholesterol in cell)
120
What is the mechanism that statins causes the increase in LDL receptors
It blocks the synthesis of cholesterol, which results in decreased inhibition of LDL receptor synthesis
121
How does a LDL receptor decrease result in more circulating LDL
- Decreased amount of LDL from the circulation into cells
| - Decreased IDL via LDL receptor leaved more IDL to be used for LDL creation
122
What is the mechanism of xanthomas forming in patients with familial hypercholesteremia
-Because the Decreased uptake via LDL receptors, scavenger receptors of nonnuclear phagocytes uptake the LDL
123
What is the result of hypercholesterolemia type 1
Uncommon and least to complete failure of synthesis of receptor proteins
124
What is the result of hypercholesterolemia type 2
Fairly common
| -Encode receptor proteins that accumulate in the ER because they can not be transported to the Golgi
125
What is the result of hypercholesterolemia type 3
Mutations affects the binding portion, so the receptors reach the surface but fail to bind LDL
126
What is the result of hypercholesterolemia type 4
Reach the membrane, can bind the LDL, but are not localized in the clathrin pits. This does not allow the internalization of the LDL
127
What is the result of hypercholesterolemia type 5
Receptors reach the membrane, bind, internalize, but are unable to be recycled normally, so they remain in the lysosomes and are degraded
128
Where are lysosomal enzymes synthesized and what is their path
Made in the ER, to the golgi, to the lysosomes (via M6P tag)
129
What is primary accumulation
Catabolism of the substrate of the missing enzyme remains incomplete, with accumulation of partially degraded metabolites in the lysosomes
130
What is secondary accumulation
Impaired autophagy causes the accumulation of autophagic products such as ubiquinated proteins and mitos.Leads to poor calcium buffering, leading to ROS and apoptosis
131
What is the mechanism of gene therapy for Gaucher disease
Mutant proteins are misfolded and unstable, therefore degraded in the ER. Addition of competitive inhibitor of enzyme binds to the enzyme, acts as template and induces proper folding
132
What are the common organ locations seen clinically in lysosomal storage disorders
Spleen and liver
133
What is the most common form of G2-gangliodisosis
Tay Sachs
134
What is the cause of Tay-Sachs
Mutations in the alpha subunit locus on chromosome 15, resulting in deficiency of hexosainidase A
135
What is the population of people at higher risk for Tay Sacs
Jews, especially Eastern European (Ashkenazic) origin
136
Accumulation of GM2 gangliosides in which neurons are commonly seen with clinical manifestations
CNS, ANS, and retina
137
What is the stain that is positive in GM2 ganglioside accumulation
Staining looking for fat, such as Oil red O and Sudan black B
138
What clinical feature in the eye is indicative of TaySacs and GM2 ganglioside accumulation
Cherry red spot on the macula
139
When do clinical features of Tay-Sachs appear and what are they usually
Begin around 6 months, and present with restless motor and mental deteriation, blindness and dementia
140
Niemann-Pick disease Type A and B is characterized by accumulation of which product
Sphingomyelin in the lysosomes
141
What is the defective gene product in Niemann-Pick disease Type A and B
Spingomyelinase
142
What are the clinical presentations in Niemann-Pick disease Type A
- Infantile form (death by age 3)
- Neuro involvement
- Visceral accumulation
- Progressive wasting
143
What are the clinical presentation of Niemann-Pick disease Type B
No CNS involvement
- Live into adulthood
- Organomegaly
144
What population of people are at higher risk for Niemann-Pick disease Type A and B
Ashkenazi jews
145
What is the location of the defect for Niemann-Pick disease Type A and B
The sphingomyelinase gene located on chromosome 11q15.4
146
The sphingomyelinase gene in Niemann-Pick disease Type A and B is preferitally expressed on which parental chromosome
Maternal, as there is paternal silencing
147
What type of mutation is seen in Niemann-Pick disease Type A
Missense
148
What type of condition will look like zebra bodies under the Electron microscopy
Laminated myelin figures “aka zebra bodies” seen in Niemann-Pick disease Type
149
Infants presenting with Niemann-Pick disease have which abdominal feature
Protuberant abdomen due to hepatosplenomegaly
150
What is the most common form of Niemann-Pick disease
Type C
151
Mutation of which gene gives rise to Niemann-Pick disease Type C
NPC1 (95% of cases) and NPC2
152
What is the gene defect result in for Niemann-Pick disease Type C
Primary defect in non-enzymatic lips transport (transports cholesterol from lysosomes to cytoplasm)
153
How will Niemann-Pick disease Type C present in clinic
Hydros fetalis, stillbirth
- neonatal hepatitis
- chronic progressive neurological damage (ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria)
154
Gaucher disease is generally caused by a defect in which enzyme, leading to accumulation of which products
Defect in glucocerebrociases, which results in excess glucocerebroside
155
What is the most common lysosomal storage disorder
Gaucher disease
156
What is the major cause pathological changes seen Gaucher disease
-Activation of macrophages and secretion of cytokines IL-1,6, TNF
157
What is the most common form of Gaucher
Type 1 (99% of cases)
158
What are the characteristics of Gaucher type 1, aka chronic nonneuronopathic
Glucocerebroside storage in mononuclear phagocytes located systemically, but without brain involvement. Major organs hit are spleen and MSK
159
Which population is at a higher risk for Gaucher Type 1
Jews of Europe
160
What is the level of glucocerebroside level in Gaucher type 1
Reduced but detectable
161
What are the characteristic of Gaucher Type 2, aka infantile acute cerebral pattern
- Neuro involvement, leading to early death
| - Heptaosplenomegaly
162
What is the level of glucocerebrosidase in Gaucher type 2
Not detectable in tissues
163
What are the characteristics of Gaucher type 3
Contains patterns of both 1 and two, with systemic and brain involvment
164
What are the microscopic characteristics of Gaucher cells
Cytoplasm with crumbled tissue paper
165
Which staining is positive with Gaucher diease
Periodic acid-Schaffer (PAS)
166
What is the main location of Gaucher cells in type 1 and where the location of accumulation
70-100% in the bone marrow producing bone erosion
167
In patients with cerebral involvement, where are catcher cells seen
Virchow-Robin spaces and arterioles
168
In Gaucher type 1, what condition is usually seen secondarily to hypersplenism
Pancytopenia and thrombocytopenia
169
Mocupolysaccaridoses (MP) are diseases with what underlying cause
Deficiency in enzymes involved in the degredation of mucopolysaccharides (glycosaminoglycans)
170
What are the examples of MPS
- Heparin sulfate
- Dermatan sulfate
- keratin sulfate
- Chondroitin sulfate
171
All MPSs are interested in which fashion, and what is the exception
All in the autosomal recessive fashion, except Hunter syndrome, which is X linked
172
MPS type 1 is characterized by deficiency in what
Deficiency in alpha-1 iduronidase (accumulation of MPS in the lysosomes)
173
What are the clinical presentations of MPSs
- Coarse facial features
- clouding of the cornea
- joint stiffness
- mental retardation
- Urinary excretion of accumulated mucopolysaccarides
174
Mucopolysaccharides accumulation in MPSs are usually found in which locations
Mononuclear phagocytic cells, endothelial cells, intimately smooth muscles cells, and fibroblasts
175
What are the commonly affected organs in MPS diseases
-spleen, liver, bone marrow, LNs, blood vessels, and heart
176
What do cells in MSP look like with microscopy
Distended and cleared cytoplasms, aka ballooning of cells
177
Wha are the common threads that run through all patients with MSPs
- hepatosplenomegaly
- valvular lesions
- subendothelial arterial deposits (coronary arteries especially)
- lesions in the brain
178
Hurler and Hunter syndrome are both characterized by the deficiency of which enzyme
-alpha-1-iduronadase
179
What is the difference between hunter and hurler syndrome
-Hurler is autosomal recessive, which hunter is X linked. Hunter is often more mild and without corneal clouding
180
What is a limit dextrin
The end product of glycogenolysis, where there is an oligosaccharide with 4 glucose on it
181
What is the function of acid maltase
Degrades glycogen in the lysosomes
182
The deficiency of enzymes involving the hepatic form will result in what
Storage and accumulation of glycogen in the liver, along with a decrease in blood glucose levels (hepatomegaly and hypoglycemia)
183
Von Gierke is what type of glycogenoses disease and what is the effected enzyme
It is hepatic form and is a deficiency in the enzyme glucose-6 phosphatase
184
What are the clinical manifestations of Von Gierke disease (Type 1)
- Stunted growth, hepatomegaly, renomegaly
- hypoglycemia (leads to convulsions)
- hyperlipidemia/hyperuricemia (gout and xanthomas develop)
- bleeding tendency due to platelet dysfunction
185
Mcardles disease (type 5) is associated with which form and what enzyme is deficient
Myopathic form and deficient in muscle phosphorylase
186
Type 7 storage disease is associated with which type and which deficient enzyme
Myopathic form with a deficiency in muscle phosphofructokinase
187
What are the general effects of a myopathic glycogen storage disease
Muscle cramps after exercise, and inability to elevate lactate blood levels (blockage in glycolysis)
188
What are the clinical presentations of myopathic glycogen storage disorders, such as McArdles (type 5)
- Painful cramps with exercise
- myoglobinuria (>50% of pts)
- exercise fails to rains lactate levels
- serum creatine kinase levels always elevated
189
What are the glycogen storage disorders associated with early death
- Deficiency of alpha-glucosidase (acid maltase)
| - lack of branching enzyme
190
What is the defect enzyme in Pompe disease (type 2)
Lysosomal glucosidase (acid maltase aka alpha glucosidase)
191
What are the morphological changes seen in Pompe diseases (type 2)
Mild hepatomegaly
Cardiomegaly (glycogen in SR)
Skeletal muscle (same as heart)
192
What are the clinical manifestations seen in Pompe’s disease (type 2)
Massive cardiomegaly, muscle hypotonia, death within 2 years
193
What is the enzyme defiance in glycogen storage disorder type 1 (Von Gierke) and what is the function of that enzyme
Glucose 6 phosphate (removes a phosphate from G6P to allow glucose to go from liver to blood)
194
What is the enzyme defiance in glycogen storage disorder type 2( Pompe) and what is the function of that enzyme
Lysosomal acid maltase (allows degredation of glycogen into glucose)
195
What is the enzyme defiance in glycogen storage disorder type 3 and what is the function of that enzyme
Debranching enzymes (takes limit dextrin into glucose)
196
What is the enzyme defiance in glycogen storage disorder type 4 and what is the function of that enzyme
Branching enzyme (allows more storage and formation of glycogen)
197
What is the enzyme defiance in glycogen storage disorder type 5 and what is the function of that enzyme
Muscle phosphorylase (allows breakdown on glycogen in muscle)
198
What is the enzyme defiance in glycogen storage disorder type 6 and what is the function of that enzyme
Liver phosphorylase (allows breakdown of glycogen in liver)
199
What is the enzyme defiance in glycogen storage disorder type 7 and what is the function of that enzyme
Phosphofructokinase (glycolysis enzymes)
200
Most familial cancers are inherited in what fashion
Autosomal dominant
201
What is the most common stain used in karyotyping
G banding, using Giema stain
202
What term Xp21.2 refers to what
X chromosome, short arm, region 2, band 1, sub-band 2
203
What is the meant by the term euploidy
Haploid number of chromosomes being normal (23)
204
What is the meant by the term aneuploidy
Haploid number of chromosomes not 23
205
What is the numbering during nondisjunction
During gametogenesis, games formed have either an extra (23+n) or missing (23-n)
206
During Fertilization, what is the result of of a normal gamate with a (n-1)
Monosomy (2n-1)
207
During Fertilization, what is the result of a normal gamete with a n+1
Trisomy (2n+1)
208
What is mosiacism
Mitotic errors in early development that give rise to two or more populations of chromosomal populations
209
What is the very common form of mosiacism
Sex chromosomes 45X/47XXX
210
Most chromosomal deletions occur where
Interstitial area, rarely terminal
211
What does the term 46,XY,del(16)(p11.2p13.1)
Deletion on short arm of 16 between regions 11.2 and 13.1
212
What does the term 46 XY,r(14) mean
Ring chromosome on 14
213
What is a paracentric inversion
Inversion involving only one are
214
What is a pericentric inversion
Inversion involving breaks on opposite sides of centromere
215
What is isochromosome
Formation resulting from one arm being lost, and the remaining arm is duplicated resulting in two short arms or two long arms
216
What is the most common isochromosome and how is is denoted
Involves the long arm of X chromosome, written i(X)(q10)
217
How would you denote a translocation
46, XX, t(2;5)(q31;p14)
| Translocation of q31 on 2 with p14 on 5
218
What is robertsonian translocation
Aka centric fusion, where there is translocation between two Afrocentric chromosomes, resulting in a very long chromosome and a very small one( which is lost)
219
What is the percentage of conceptions with an abnormal chromosome
7.5, most not compatible with life
220
What percentage of Down syndrome is caused by trisomy 21
95%, so their chromosome count is 47
221
What is the most common cause of trisomy and Down syndrome
Meiotic nondisjuction
222
Where does most of the meiotic nondisjunction occur
The ovum of the mother (95% in case of trisomy 21)
223
What percentage of Down syndrome cases involve a Robertsonian translocation of the long arm of 21 to Afrocentric chromosome
4%
224
In the case of mosiac Down syndrome or translocation, what is the maternal age involvement
There is non
225
What are the general features of pts with Down syndrome
- flat facial profile
- Oblique palpebral fissures
- epicanthic folds
226
What is the majority of IQ ranges for patients with Downs and what is the percentage
80% between IQ of 25 to 50
227
What percentage of patients with Down syndrome have a congenital heart defect
40%
228
What are the common involvement of heart defects in patients with Down syndrome
-optimum primum, ASD, AV valves, VSD
229
What is the major cause of death in infancy and early childhood for patients with Down syndrome
Cardiac problems
230
What aretrisomy 21 Patients at a higher risk of developing
```
Acute leukemia (10-20x more likely)
-Most commonly megakaryoblastic leukemia
```
231
Virtually all trisomy 21 patients above the age of 40 develop what
Neuropathic disorder characteristic of Alzheimer disease
232
What are the main features of trisomy 21
- Abundant neck skin
- Simian crease
- Heart defects
- Intestinal stenosis
- Umbilical hernia
- hypotonia
- Gap between toes 1 and 2
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What are the clinical features of trisomy 18: Edwards syndrome
- Prominent occiput
- Micrognathia (small jaw)
- Low set ears and short neck
- overlapping fingers
- Congeital heart defects and kidney malformations (horseshoe)
- limited hip abduction and rocker bottom feet
234
What are the clinical features of Trisomy 13: Patau syndrome
-Microphthalmia
-Microcephaly
-polydactyly (increased finger number)
-cleft lip and palate
-Cardiac and renal defects
Umbilical herniation
-Rocker bottom feet
235
Patients with 22q11.2 deletion syndrome are at a higher risk to develop with mental disorder
Schizophrenia (25% of all pts) and bipolar disorder
236
In those patients with 22q11.2 deletions, what percentage had been diagnosed with other disorders
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DiGeorge (90%)
Velocardiofacial syndrome (80%)
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237
Which transcription factor is highly correlated with deletions in 22q11.2
TBX1, which targets PAX9
238
Which chromosomes are more commonly disrupted and which are more tolerated
Sex chromosomes see more common involved in genetic diseases, and they are also better tolerated
239
What is the process of heteropyknosis
Inactivation of the other X chromosome
240
When does the silencing of the X chromosome occur
Randomly selected X is inactivated in all cells of blastocyst about day 5.5
241
Which parts of X escape silencing and what percentage of them do
21% of genes on Xp and 3% on Xq escape silencing
242
Where is the SRY gene located
The distal short arm of Y chromosome
243
When does Klinefelter syndrome occur
-When there are 2 or more X chromosomes and one or more Y
244
What is the most common cause of hypogonadism in males
Klinefelter syndrome (1 in 660)
245
What are the physical characteristics in patients with Klinefelter syndrome
- Increased length between soles and pubic bone (elongated body)
- small atropic testis and small penis
- lack of secondary male characteristics
- gynocomastia
246
What conditions are patients with Klinefelter syndrome at a higher risk of developing
- Type 2 diabetes
- metabolic syndrome
- insulin resistance
- Osteoporosis and fractures
- Mitral valve prolapse
- Male breast cancer (20 times more common)
- SLE and other autoimmune
- Extragonal germ cell tumors
247
What is the cardiac involvement in patients with Klinefelter syndrome
Mitral valve prolapse (50% of pts)
248
What is the genetic makeup of majority of Klinefelter syndrome patients and what is the percentage
90% are 47,XXY
249
Klinefelter is the result of which type of genetic mistake
Meiotic nondisjuction in one of parents
250
What is the cause of pathogenesis of Klinefelter syndrome
- Overexpression of X genes that evade silencing (since there are 2 sets of genes escaping silencing)
- androgen receptor sensitivity
251
Where does the testosterone receptor map from
X chromosome
252
What repeats does the testosterone receptor encompass
CAG repeats
253
What length of CAG repeats are more sensitive in androgen receptors
Shorter repeats are more sensitive to testosterone
254
In Klinefelter syndrome, which length of CAG repeats is silenced
The shorter repeat is silenced, so the less sensitive receptor is expressed
255
What percentage of Turner syndrome pts are missing an X chromosome
57% are missing, resulting in 45,X
256
What are the structural abnormalities that result in Turner
1) isochromosomal of long arm and loss of small (46,X,i(X)(q10)
2) deletions of portions of both long and short resulting in ring(46,X,r(X))
3) deletions of short or long arm (46X,del(Xq)) or 46X,del(Xp)
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What is the genetic makeup of Turner syndrome
45,X (truely no nonmosiac Turner syndrome patients)
258
What percentage of Turner syndrome patients have Y chromosomes
5-10%
259
In Turner syndrome patients with a Y chrosome, what are the at higher risk of developing
Gonadal tumor aka gonadoblastoma
260
What do Turner syndrome patients present with during infancy
- edema of the dorsum of hand and foot (due to lymph stasis)
| - Swelling of the nape of neck (due to cystic hygroma)
261
What is the rate of heart issues with Turner syndrome pts
- 25 to 50% develop congenital heart defects (left CV abnormalities, predictable coarction of aorta and bicuspid)
- Most cause of increased mortality in children
262
What is the single most important cause of amenorrhea
Turner syndrome
263
What is the correlation of hypothyroid and Turner syndrome
50% develop Abs to thyroid, leading to hypothyroidism
264
What is Turner syndrome assoacited with metabolically
-GLucose intolerance, obesity, insulin resistance
265
What is the importance of insulin resistance seen in pts with Turner syndrome
Growth hormone that is given to pts with Turner syndrome will worsens the insulin resistance
266
What are the physical characteristics seen in Turner syndrome pts
- Short stature
- Low posterior hairline with webbing of neck
- Coarction of aorta
- Cubitus valgus
- Streak ovaries/infertility/amenorrhea
- Pigmented Nevi
- Peripheral edema at birth
267
Is Turner syndrome assoacited with maternal or paternal X chromosomes
Paternal, as the lone X is maternal in 75% or patients
268
What is the level of ovum in Turner syndrome
Fetal ovaries develop normally, but lack of second X leads to loss of oocytes, completed by year 2( menopause before menarche)
269
What are the genes involved in Turner syndrome and where are they located
Short stature homeobox (SHOX) gene at Xp22.33
