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Robbins Pathology MOD1 (Chptr 1-6) > Chapter 5 > Flashcards

Chapter 5 Flashcards

1
Q

What percentage of spontaneous abortions have chromosomal abnormalities

A

50%

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2
Q

What percentage of newborns contain a gross chromosomal abnormality

A

1%

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3
Q

Will mutations in somatic cells cause defects in progeny

A

No

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4
Q

What is a single base nucleotide substitution

A

The base is changes, potentially resulting in the change of a single amino acid

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5
Q

What is a missense mutation

A

Single base mutation resulting in the change of amino acid

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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

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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

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8
Q

What is a nonsense mutation

A

The base change results in a stop codon

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9
Q

What is B0-thalassemia

A

Beta-globin chain is prematurely stoped due to nonsense mutation, resulting in immediate degradation

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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

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11
Q

What is a frameshift mutation

A

Change in amino acid number (addition or deletion) of a nonmultiple of 3

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12
Q

What is the usual result of a frameshift mutation

A

Variable number of incorrect amino acids followed by a premature stop codon

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13
Q

Which bases do almost all trinucleotide repeats incorporate

A

Cytosine and Guanine

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14
Q

What type of mutation results in taysachs disease

A

Frameshift mutation (addition of 4 amino acids)

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15
Q

What type of mutation results in the blood allele Group O

A

Frameshift mutation from the addition of a single nucleotide

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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

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17
Q

What does the term congenital mean

A

Means born with, but does not have to be familial (ex congenital syphilis)

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18
Q

What are virtually all Mendelian disorders

A

Mutations in single genes that have large effects

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19
Q

What percentage of non expressive recessive mutations arefamilial

A

80-85%

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20
Q

Sickle cell anemia is caused by what

A

Substitution of normal hemoblobin (HbA) with hemoglobin S (HbS)

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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

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22
Q

What are two examples of codominance

A

Blood group compatibility and MHC

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23
Q

What is pleiotropism

A

A single gene mutant leads to many effects

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24
Q

What is genetic heterogeneity

A

Mutations at several genetic can produce the same trait

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25
Q

Sickle cell mutation is described as what

A

Pleiotropism

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26
Q

How is sickle cell an example of pleiotropism

A

The disfigured sickle cells can log jam vessels, leading to splenic fibrosis, organ infarcts, and bone changes

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27
Q

Mutations involving a single gene follow which of three patterns

A

1) Autosomal dominant
2) Autosomal recessive
3) X-linked

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28
Q

How is it possible to have an autosomal dominant gene expressed in a chid but not in a parent

A

There is a new mutation in either the sperm of the egg they were derived from

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29
Q

In the case of a child who inherited an autosomal dominant trait from unsympotomatic patients, how likely are subsequent siblings to develop the disease

A

Not at all, as siblings are not effected not at higher risk

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30
Q

If a disease causes a decrease in reproductivity, how is the trait passed on

A

Usually a result of a new mutation. Commonly seen in germ cells of older father

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31
Q

What is incomplete penetrance

A

Inheriting the mutant gene, but phenotypically normal

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32
Q

Neurofibromatosis type 1 presents what type of expressivity

A

Variable expressivity

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33
Q

What is the result of loss of 50% of LDL receptors

A

Secondary elevation of cholesterol that predisposes pt to atherosclerosis

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34
Q

What is dominant negative

A

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

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35
Q

How is collagen an example of dominant negative

A

Collagen is a trimeric structure. Loss of function on one of the strands leads to the inability to form the whole structure

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36
Q

Transmission of a disorder produced by a gain of function mutation is almost always what

A

Autosomal dominant

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37
Q

How is Huntington disease an example of gain of function disease

A

Mutation gives rise to abnormal protein called Huntington, which is toxic to neurons, so even a heterozygote can develop disease

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38
Q

What type of disorder makes up the largest category of disorders

A

Autosomal recessive

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39
Q

Almost all inborn errors of metabolism are what kind of disorder

A

Autosomal recessive

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40
Q

What are the characteristic findings of autosomal recessive that separate them from other disorders

A
  • Complete penetrance
  • onset early in life
  • more uniform expression
  • New mutations are rarely seen clinically
  • Many of the genes encode enzymes
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41
Q

Why is the there no Y linked inheritance

A

Because disorders on Y chromosome usually lead to infertile males

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42
Q

Males are considered what with regards to X chromosome

A

Hemizygous for X linked mutant genes

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43
Q

What is the rate of inheritance of a positive X linked disorder male

A

Will not pass to male sons, all daughters are carriers

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44
Q

How is a heterozygous female able to express phenotypically the X linked disorder

A

Random inactivation of an X chromome could cause the normal X to be silenced

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45
Q

What is the heritability of G6PD deficiency

A

X linked

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46
Q

How does G6PD deficiency affect females who are heterozygous

A

X linked trait, so affects males via hemolysis. Females will have some RBCs that are enzyme deficient and can still result in hemolysis

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47
Q

What is the heritability pattern of an X linked dominant disorder from the father

A

Gives to all of the daughters, and none of the sons

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48
Q

What is the example of X llinker dominant disorders

A

Vitamin D resistant rickets

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49
Q

What is type of heritability disorder for Huntington disease

A

Autosomal dominant

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50
Q

What is type of heritability disorder for Neurofibromatosis

A

Autosomal dominant

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51
Q

What is type of heritability disorder for Myotonic dystrophy

A

Autosomal dominant

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52
Q

What is type of heritability disorder for Tuberous sclerosis

A

Autosomal dominant

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53
Q

What is type of heritability disorder for Polycystic kidney disease

A

Autosomal dominant

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54
Q

What is the result from a mutation resulting in the decreased synthesis of an enzyme with reduced activity or reduced amount of normal enzyme

A

Metabolic block

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55
Q

The mutation in galactose-1 phosphate uridyltransferase results in the buildup of which product

A

Galactose

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56
Q

What is the result in the defect in tyrosinase

A

Deficiency in melanin, leading to albinism

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57
Q

What is the result of the metabolic block in alpha1-antitrypsin deficiency

A

Failure to inactivate neutrophil elastase in lungs

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58
Q

What is the result of a mutated LDL receptor in familial hypercholesterolemia

A

Reduced synthesis of LDL, decreased transport of LDL into cell, increased cholesterol in blood, increased cholesterol synthesis

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59
Q

What is the general characteristics of thalassemias

A

Mutations in globulin genes that result in a decrease in the amount of globulin chains made

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60
Q

What drug is contraindicated in G6PD deficiency

A

Primaquine

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61
Q

What is the result of administration of antimalarial drug primaquine to a G6PD deficient patient

A

Hemolytic anemia

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62
Q

What the three systems mainly affected by Marian syndrome

A

Skeleton, eyes, and cardiovascular system

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63
Q

What is the prevalence of Marian syndrome

A

1 in 5000

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64
Q

What is the percentage of Marian syndrome cases that are familial and transmitted by autosomal dominant inheritance

A

70 to 85%

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65
Q

What does the pathogenesis of Marfan come from

A

Defect in extracellular glycoproteins called fibrillin 1

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66
Q

What are the two general mechanisms that Marfans syndrome results in weakened connective tissue

A
  • Loss of structural support in micro fibril rich connective tissue
  • Excessive TGF beta signaling
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67
Q

The fibrils that are affected in Marfans serve which purpose

A

Act as scaffolding for tropoelastin, which is deposited to from elastic fibers

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68
Q

What are the main locations of elasticity loss in Marfans

A

Aorta, ligaments, ciliary zonules (supporting the lens)

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69
Q

FBN1, which codes for fibrillin-1, is located on which chromosome location

A

15q21.1

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70
Q

FBN2, which codes for fibrillin-2, is located on which chromosome location

A

5q23.31

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71
Q

Mutations in which gene is the underlying mechanism of pathogenesis in Marfans

A

FBN1

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72
Q

What does a mutation in FBN2 cause

A

Congentical contractural arachnodactyly

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73
Q

What is congenital contractural arachnodactyly caused by and what is the pattern of inheritance

A

Autosomal dominant, mutation in FBN2

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74
Q

What is haploinsufficiency

A

Reduction of fibrillin content below threshold, resulting in connective tissue weakness

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75
Q

What is the correlation between TGFbeta levels and Marfans

A

Marfans has excessive TGFbeta due to loss of microfibrils. Increases MMP and the loss of ECM

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76
Q

What are the normal clinical features of a healthy patient with Marfans

A

-Tall, with long extremities, tapering fingers and toes. Double jointed with a hyperextended thumb. Frontal eminences and prominent supraorbital ridges.

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77
Q

What will a patient with Marfans present with regards to spinal deformities

A

Kyphosis, scoliosis, rotation or slipping of the lumbar vertebra

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78
Q

What will a patient with Marfan present with regards to the chest

A

Lecture excavatum is pigeon breasted

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79
Q

What will a patient with Marfan present with regards to ocular changes

A

Ectopia lentis, aka bilateral subluxation or dislocation of the lens

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80
Q

A patient presenting with ectopic lentis, or outward and upward dislocation of the lens should be checked for which condition

A

Marfans

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81
Q

What are the commonly seen CV findings in a pt with Marfans

A

Mitral valve prolapse, dilation of the ascending aorta (due to cystic medionecrosis)

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82
Q

What is the common cause of death in Marfans patients and what is the percentage

A

Aortic dissection/hemorrhage in 30-45% of pts

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83
Q

What is required for the diagnosis of Marfans

A

Major involvement of two organ systems (MSK, CV, Ocular, Skin) and minor involvement of another organ

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84
Q

What is the main treatment for Marfans

A

Beta blockers to decrease HR and aortic stress

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85
Q

Ehlers-Danlos Syndrome (EDS) is caused by which general underlying condition

A

Defect in the synthesis or structure of collagen

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86
Q

Which of Mendelian patterns does Ehlers-Danlos Syndrome (EDS) encompass

A

All 3 principles

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87
Q

What are the locations of structures most affected by Ehlers-Danlos Syndrome (EDS)

A

skin, ligaments and joints

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88
Q

What are the serious complications seen in patients with Ehlers-Danlos Syndrome (EDS)

A

-Rupture of colon and large arteries, cornea and retinal detachment, diaphragmatic herniation

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89
Q

What is the most common form of Ehlers-Danlos Syndrome (EDS)

A

Lyphoscoliosis type

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90
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 1

A

Aka classic

Autosomal dominant

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91
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 2

A

Autosomal dominant

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92
Q

What is the herititability of Ehlers-Danlos Syndrome (EDS) type 3

A

Aka hypermobility’

Autosomal dominant

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93
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 4

A

Aka vascular

Autosomal dominant

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94
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 6

A

Aka hyphoscoliosis

Autosomal recessive

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95
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7a/b

A

Aka arthrochlasias

Autosomal dominant

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96
Q

What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7c

A

Aka dermatosparaxis

Autosomal recessive

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97
Q

What is the mutation coding in Ehlers-Danlos Syndrome (EDS) kyphoscoliosis

A

Lysyl hydroxylase (can not hydroxylate lysine residues)

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98
Q

What is the mutation code in Ehlers-Danlos Syndrome (EDS) vascular type

A

COL3A1, giving rise to abnormalities in collagen type 3

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99
Q

What is the defect in Ehlers-Danlos Syndrome (EDS) arthrochalasia type

A

COL1A1 and COLA1A2, which is defect in conversion from procollagen to collagen via defect in the pro-alpha chains (resist cleavage)

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100
Q

What is the defect in Ehlers-Danlos Syndrome (EDS) dermatosparaxis type

A

Mutations in procollagen-N-peptidase gene, preventing cleavage from procollagen to collagen

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101
Q

What is the defect in Ehlers-Danlos Syndrome (EDS) classic type

A

COL5A1 and COL5A2

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102
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 1/2

A

Skin and joint hyper mobility, strophic scars, easy bruising

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103
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 3

A

Joint hypermobility, pain, dislocations

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104
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 4

A

Thin skin, arterial and uterine rupture, bruising, small joint hyperextendability

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105
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 6

A

Hypotonia, joint laxity, congenital scoliosis, ocular fragility

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106
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7a/b

A

Severe joint hyper mobility, skin changes, scoliosis, bruising

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107
Q

What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7c

A

Severe skin fragility, cutis lata, bruising

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108
Q

What is the level of plasma cholesterol levels in homozygous individuals

A

5-6 times the normal

109
Q

What percentage of the body’s cholesterol is in plasma and how is it circulating

A

7% of total, mostly in LDL

110
Q

What is the steps of cholesterol synthesis

A

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
Q

What is the immediate and main source of LDL

112
Q

What are the two fates of IDL

A

1) Taken up by liver to make more VLDL

2) Formed into cholesterol rich LDL

113
Q

What is the receptor used for uptake of IDL and what is it recognizing

A

LDL receptor and recognized ApOE and Apo100

114
Q

What is the major location of LDL clearance and what is the percentage

A

70% by the liver

115
Q

In lysosomes, what are the lipoproteins and cholesteryl esters broken down into

A

Lipoprotein into free amino acids

Cholesteryl esters into free cholesterol

116
Q

What is the mechanism that free cholesterol enters the cytoplasm

A

Via NPC1 and NPC2, which transports them

117
Q

What effect does cholesterol have on synthesis of cholesterol, and what is the mechanism

A

Inhibits synthesis by inhibiting activity of HMG-COA reductase

118
Q

What effect does cholesterol have on the enzyme acyl-coenzyme A

A

Increases activity, which is A cholesterol acyltransferase (favors esterification and storage of excess cholesterol)

119
Q

What affect does cholesterol have on LDL receptor production

A

Inhibits (protection from excessive cholesterol in cell)

120
Q

What is the mechanism that statins causes the increase in LDL receptors

A

It blocks the synthesis of cholesterol, which results in decreased inhibition of LDL receptor synthesis

121
Q

How does a LDL receptor decrease result in more circulating LDL

A
  • Decreased amount of LDL from the circulation into cells

- Decreased IDL via LDL receptor leaved more IDL to be used for LDL creation

122
Q

What is the mechanism of xanthomas forming in patients with familial hypercholesteremia

A

-Because the Decreased uptake via LDL receptors, scavenger receptors of nonnuclear phagocytes uptake the LDL

123
Q

What is the result of hypercholesterolemia type 1

A

Uncommon and least to complete failure of synthesis of receptor proteins

124
Q

What is the result of hypercholesterolemia type 2

A

Fairly common

-Encode receptor proteins that accumulate in the ER because they can not be transported to the Golgi

125
Q

What is the result of hypercholesterolemia type 3

A

Mutations affects the binding portion, so the receptors reach the surface but fail to bind LDL

126
Q

What is the result of hypercholesterolemia type 4

A

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
Q

What is the result of hypercholesterolemia type 5

A

Receptors reach the membrane, bind, internalize, but are unable to be recycled normally, so they remain in the lysosomes and are degraded

128
Q

Where are lysosomal enzymes synthesized and what is their path

A

Made in the ER, to the golgi, to the lysosomes (via M6P tag)

129
Q

What is primary accumulation

A

Catabolism of the substrate of the missing enzyme remains incomplete, with accumulation of partially degraded metabolites in the lysosomes

130
Q

What is secondary accumulation

A

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
Q

What is the mechanism of gene therapy for Gaucher disease

A

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
Q

What are the common organ locations seen clinically in lysosomal storage disorders

A

Spleen and liver

133
Q

What is the most common form of G2-gangliodisosis

134
Q

What is the cause of Tay-Sachs

A

Mutations in the alpha subunit locus on chromosome 15, resulting in deficiency of hexosainidase A

135
Q

What is the population of people at higher risk for Tay Sacs

A

Jews, especially Eastern European (Ashkenazic) origin

136
Q

Accumulation of GM2 gangliosides in which neurons are commonly seen with clinical manifestations

A

CNS, ANS, and retina

137
Q

What is the stain that is positive in GM2 ganglioside accumulation

A

Staining looking for fat, such as Oil red O and Sudan black B

138
Q

What clinical feature in the eye is indicative of TaySacs and GM2 ganglioside accumulation

A

Cherry red spot on the macula

139
Q

When do clinical features of Tay-Sachs appear and what are they usually

A

Begin around 6 months, and present with restless motor and mental deteriation, blindness and dementia

140
Q

Niemann-Pick disease Type A and B is characterized by accumulation of which product

A

Sphingomyelin in the lysosomes

141
Q

What is the defective gene product in Niemann-Pick disease Type A and B

A

Spingomyelinase

142
Q

What are the clinical presentations in Niemann-Pick disease Type A

A
  • Infantile form (death by age 3)
  • Neuro involvement
  • Visceral accumulation
  • Progressive wasting
143
Q

What are the clinical presentation of Niemann-Pick disease Type B

A

No CNS involvement

  • Live into adulthood
  • Organomegaly
144
Q

What population of people are at higher risk for Niemann-Pick disease Type A and B

A

Ashkenazi jews

145
Q

What is the location of the defect for Niemann-Pick disease Type A and B

A

The sphingomyelinase gene located on chromosome 11q15.4

146
Q

The sphingomyelinase gene in Niemann-Pick disease Type A and B is preferitally expressed on which parental chromosome

A

Maternal, as there is paternal silencing

147
Q

What type of mutation is seen in Niemann-Pick disease Type A

148
Q

What type of condition will look like zebra bodies under the Electron microscopy

A

Laminated myelin figures “aka zebra bodies” seen in Niemann-Pick disease Type

149
Q

Infants presenting with Niemann-Pick disease have which abdominal feature

A

Protuberant abdomen due to hepatosplenomegaly

150
Q

What is the most common form of Niemann-Pick disease

151
Q

Mutation of which gene gives rise to Niemann-Pick disease Type C

A

NPC1 (95% of cases) and NPC2

152
Q

What is the gene defect result in for Niemann-Pick disease Type C

A

Primary defect in non-enzymatic lips transport (transports cholesterol from lysosomes to cytoplasm)

153
Q

How will Niemann-Pick disease Type C present in clinic

A

Hydros fetalis, stillbirth

  • neonatal hepatitis
  • chronic progressive neurological damage (ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria)
154
Q

Gaucher disease is generally caused by a defect in which enzyme, leading to accumulation of which products

A

Defect in glucocerebrociases, which results in excess glucocerebroside

155
Q

What is the most common lysosomal storage disorder

A

Gaucher disease

156
Q

What is the major cause pathological changes seen Gaucher disease

A

-Activation of macrophages and secretion of cytokines IL-1,6, TNF

157
Q

What is the most common form of Gaucher

A

Type 1 (99% of cases)

158
Q

What are the characteristics of Gaucher type 1, aka chronic nonneuronopathic

A

Glucocerebroside storage in mononuclear phagocytes located systemically, but without brain involvement. Major organs hit are spleen and MSK

159
Q

Which population is at a higher risk for Gaucher Type 1

A

Jews of Europe

160
Q

What is the level of glucocerebroside level in Gaucher type 1

A

Reduced but detectable

161
Q

What are the characteristic of Gaucher Type 2, aka infantile acute cerebral pattern

A
  • Neuro involvement, leading to early death

- Heptaosplenomegaly

162
Q

What is the level of glucocerebrosidase in Gaucher type 2

A

Not detectable in tissues

163
Q

What are the characteristics of Gaucher type 3

A

Contains patterns of both 1 and two, with systemic and brain involvment

164
Q

What are the microscopic characteristics of Gaucher cells

A

Cytoplasm with crumbled tissue paper

165
Q

Which staining is positive with Gaucher diease

A

Periodic acid-Schaffer (PAS)

166
Q

What is the main location of Gaucher cells in type 1 and where the location of accumulation

A

70-100% in the bone marrow producing bone erosion

167
Q

In patients with cerebral involvement, where are catcher cells seen

A

Virchow-Robin spaces and arterioles

168
Q

In Gaucher type 1, what condition is usually seen secondarily to hypersplenism

A

Pancytopenia and thrombocytopenia

169
Q

Mocupolysaccaridoses (MP) are diseases with what underlying cause

A

Deficiency in enzymes involved in the degredation of mucopolysaccharides (glycosaminoglycans)

170
Q

What are the examples of MPS

A
  • Heparin sulfate
  • Dermatan sulfate
  • keratin sulfate
  • Chondroitin sulfate
171
Q

All MPSs are interested in which fashion, and what is the exception

A

All in the autosomal recessive fashion, except Hunter syndrome, which is X linked

172
Q

MPS type 1 is characterized by deficiency in what

A

Deficiency in alpha-1 iduronidase (accumulation of MPS in the lysosomes)

173
Q

What are the clinical presentations of MPSs

A
  • Coarse facial features
  • clouding of the cornea
  • joint stiffness
  • mental retardation
  • Urinary excretion of accumulated mucopolysaccarides
174
Q

Mucopolysaccharides accumulation in MPSs are usually found in which locations

A

Mononuclear phagocytic cells, endothelial cells, intimately smooth muscles cells, and fibroblasts

175
Q

What are the commonly affected organs in MPS diseases

A

-spleen, liver, bone marrow, LNs, blood vessels, and heart

176
Q

What do cells in MSP look like with microscopy

A

Distended and cleared cytoplasms, aka ballooning of cells

177
Q

Wha are the common threads that run through all patients with MSPs

A
  • hepatosplenomegaly
  • valvular lesions
  • subendothelial arterial deposits (coronary arteries especially)
  • lesions in the brain
178
Q

Hurler and Hunter syndrome are both characterized by the deficiency of which enzyme

A

-alpha-1-iduronadase

179
Q

What is the difference between hunter and hurler syndrome

A

-Hurler is autosomal recessive, which hunter is X linked. Hunter is often more mild and without corneal clouding

180
Q

What is a limit dextrin

A

The end product of glycogenolysis, where there is an oligosaccharide with 4 glucose on it

181
Q

What is the function of acid maltase

A

Degrades glycogen in the lysosomes

182
Q

The deficiency of enzymes involving the hepatic form will result in what

A

Storage and accumulation of glycogen in the liver, along with a decrease in blood glucose levels (hepatomegaly and hypoglycemia)

183
Q

Von Gierke is what type of glycogenoses disease and what is the effected enzyme

A

It is hepatic form and is a deficiency in the enzyme glucose-6 phosphatase

184
Q

What are the clinical manifestations of Von Gierke disease (Type 1)

A
  • Stunted growth, hepatomegaly, renomegaly
  • hypoglycemia (leads to convulsions)
  • hyperlipidemia/hyperuricemia (gout and xanthomas develop)
  • bleeding tendency due to platelet dysfunction
185
Q

Mcardles disease (type 5) is associated with which form and what enzyme is deficient

A

Myopathic form and deficient in muscle phosphorylase

186
Q

Type 7 storage disease is associated with which type and which deficient enzyme

A

Myopathic form with a deficiency in muscle phosphofructokinase

187
Q

What are the general effects of a myopathic glycogen storage disease

A

Muscle cramps after exercise, and inability to elevate lactate blood levels (blockage in glycolysis)

188
Q

What are the clinical presentations of myopathic glycogen storage disorders, such as McArdles (type 5)

A
  • Painful cramps with exercise
  • myoglobinuria (>50% of pts)
  • exercise fails to rains lactate levels
  • serum creatine kinase levels always elevated
189
Q

What are the glycogen storage disorders associated with early death

A
  • Deficiency of alpha-glucosidase (acid maltase)

- lack of branching enzyme

190
Q

What is the defect enzyme in Pompe disease (type 2)

A

Lysosomal glucosidase (acid maltase aka alpha glucosidase)

191
Q

What are the morphological changes seen in Pompe diseases (type 2)

A

Mild hepatomegaly
Cardiomegaly (glycogen in SR)
Skeletal muscle (same as heart)

192
Q

What are the clinical manifestations seen in Pompe’s disease (type 2)

A

Massive cardiomegaly, muscle hypotonia, death within 2 years

193
Q

What is the enzyme defiance in glycogen storage disorder type 1 (Von Gierke) and what is the function of that enzyme

A

Glucose 6 phosphate (removes a phosphate from G6P to allow glucose to go from liver to blood)

194
Q

What is the enzyme defiance in glycogen storage disorder type 2( Pompe) and what is the function of that enzyme

A

Lysosomal acid maltase (allows degredation of glycogen into glucose)

195
Q

What is the enzyme defiance in glycogen storage disorder type 3 and what is the function of that enzyme

A

Debranching enzymes (takes limit dextrin into glucose)

196
Q

What is the enzyme defiance in glycogen storage disorder type 4 and what is the function of that enzyme

A

Branching enzyme (allows more storage and formation of glycogen)

197
Q

What is the enzyme defiance in glycogen storage disorder type 5 and what is the function of that enzyme

A

Muscle phosphorylase (allows breakdown on glycogen in muscle)

198
Q

What is the enzyme defiance in glycogen storage disorder type 6 and what is the function of that enzyme

A

Liver phosphorylase (allows breakdown of glycogen in liver)

199
Q

What is the enzyme defiance in glycogen storage disorder type 7 and what is the function of that enzyme

A

Phosphofructokinase (glycolysis enzymes)

200
Q

Most familial cancers are inherited in what fashion

A

Autosomal dominant

201
Q

What is the most common stain used in karyotyping

A

G banding, using Giema stain

202
Q

What term Xp21.2 refers to what

A

X chromosome, short arm, region 2, band 1, sub-band 2

203
Q

What is the meant by the term euploidy

A

Haploid number of chromosomes being normal (23)

204
Q

What is the meant by the term aneuploidy

A

Haploid number of chromosomes not 23

205
Q

What is the numbering during nondisjunction

A

During gametogenesis, games formed have either an extra (23+n) or missing (23-n)

206
Q

During Fertilization, what is the result of of a normal gamate with a (n-1)

A

Monosomy (2n-1)

207
Q

During Fertilization, what is the result of a normal gamete with a n+1

A

Trisomy (2n+1)

208
Q

What is mosiacism

A

Mitotic errors in early development that give rise to two or more populations of chromosomal populations

209
Q

What is the very common form of mosiacism

A

Sex chromosomes 45X/47XXX

210
Q

Most chromosomal deletions occur where

A

Interstitial area, rarely terminal

211
Q

What does the term 46,XY,del(16)(p11.2p13.1)

A

Deletion on short arm of 16 between regions 11.2 and 13.1

212
Q

What does the term 46 XY,r(14) mean

A

Ring chromosome on 14

213
Q

What is a paracentric inversion

A

Inversion involving only one are

214
Q

What is a pericentric inversion

A

Inversion involving breaks on opposite sides of centromere

215
Q

What is isochromosome

A

Formation resulting from one arm being lost, and the remaining arm is duplicated resulting in two short arms or two long arms

216
Q

What is the most common isochromosome and how is is denoted

A

Involves the long arm of X chromosome, written i(X)(q10)

217
Q

How would you denote a translocation

A

46, XX, t(2;5)(q31;p14)

Translocation of q31 on 2 with p14 on 5

218
Q

What is robertsonian translocation

A

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
Q

What is the percentage of conceptions with an abnormal chromosome

A

7.5, most not compatible with life

220
Q

What percentage of Down syndrome is caused by trisomy 21

A

95%, so their chromosome count is 47

221
Q

What is the most common cause of trisomy and Down syndrome

A

Meiotic nondisjuction

222
Q

Where does most of the meiotic nondisjunction occur

A

The ovum of the mother (95% in case of trisomy 21)

223
Q

What percentage of Down syndrome cases involve a Robertsonian translocation of the long arm of 21 to Afrocentric chromosome

224
Q

In the case of mosiac Down syndrome or translocation, what is the maternal age involvement

A

There is non

225
Q

What are the general features of pts with Down syndrome

A
  • flat facial profile
  • Oblique palpebral fissures
  • epicanthic folds
226
Q

What is the majority of IQ ranges for patients with Downs and what is the percentage

A

80% between IQ of 25 to 50

227
Q

What percentage of patients with Down syndrome have a congenital heart defect

228
Q

What are the common involvement of heart defects in patients with Down syndrome

A

-optimum primum, ASD, AV valves, VSD

229
Q

What is the major cause of death in infancy and early childhood for patients with Down syndrome

A

Cardiac problems

230
Q

What aretrisomy 21 Patients at a higher risk of developing

A 
Acute leukemia (10-20x more likely)
-Most commonly megakaryoblastic leukemia
231
Q

Virtually all trisomy 21 patients above the age of 40 develop what

A

Neuropathic disorder characteristic of Alzheimer disease

232
Q

What are the main features of trisomy 21

A
  • Abundant neck skin
  • Simian crease
  • Heart defects
  • Intestinal stenosis
  • Umbilical hernia
  • hypotonia
  • Gap between toes 1 and 2
233
Q

What are the clinical features of trisomy 18: Edwards syndrome

A
  • 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
Q

What are the clinical features of Trisomy 13: Patau syndrome

A

-Microphthalmia
-Microcephaly
-polydactyly (increased finger number)
-cleft lip and palate
-Cardiac and renal defects
Umbilical herniation
-Rocker bottom feet

235
Q

Patients with 22q11.2 deletion syndrome are at a higher risk to develop with mental disorder

A

Schizophrenia (25% of all pts) and bipolar disorder

236
Q

In those patients with 22q11.2 deletions, what percentage had been diagnosed with other disorders

A 
DiGeorge (90%)
Velocardiofacial syndrome (80%)
237
Q

Which transcription factor is highly correlated with deletions in 22q11.2

A

TBX1, which targets PAX9

238
Q

Which chromosomes are more commonly disrupted and which are more tolerated

A

Sex chromosomes see more common involved in genetic diseases, and they are also better tolerated

239
Q

What is the process of heteropyknosis

A

Inactivation of the other X chromosome

240
Q

When does the silencing of the X chromosome occur

A

Randomly selected X is inactivated in all cells of blastocyst about day 5.5

241
Q

Which parts of X escape silencing and what percentage of them do

A

21% of genes on Xp and 3% on Xq escape silencing

242
Q

Where is the SRY gene located

A

The distal short arm of Y chromosome

243
Q

When does Klinefelter syndrome occur

A

-When there are 2 or more X chromosomes and one or more Y

244
Q

What is the most common cause of hypogonadism in males

A

Klinefelter syndrome (1 in 660)

245
Q

What are the physical characteristics in patients with Klinefelter syndrome

A
  • Increased length between soles and pubic bone (elongated body)
  • small atropic testis and small penis
  • lack of secondary male characteristics
  • gynocomastia
246
Q

What conditions are patients with Klinefelter syndrome at a higher risk of developing

A
  • 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
Q

What is the cardiac involvement in patients with Klinefelter syndrome

A

Mitral valve prolapse (50% of pts)

248
Q

What is the genetic makeup of majority of Klinefelter syndrome patients and what is the percentage

A

90% are 47,XXY

249
Q

Klinefelter is the result of which type of genetic mistake

A

Meiotic nondisjuction in one of parents

250
Q

What is the cause of pathogenesis of Klinefelter syndrome

A
  • Overexpression of X genes that evade silencing (since there are 2 sets of genes escaping silencing)
  • androgen receptor sensitivity
251
Q

Where does the testosterone receptor map from

A

X chromosome

252
Q

What repeats does the testosterone receptor encompass

A

CAG repeats

253
Q

What length of CAG repeats are more sensitive in androgen receptors

A

Shorter repeats are more sensitive to testosterone

254
Q

In Klinefelter syndrome, which length of CAG repeats is silenced

A

The shorter repeat is silenced, so the less sensitive receptor is expressed

255
Q

What percentage of Turner syndrome pts are missing an X chromosome

A

57% are missing, resulting in 45,X

256
Q

What are the structural abnormalities that result in Turner

A

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)

257
Q

What is the genetic makeup of Turner syndrome

A

45,X (truely no nonmosiac Turner syndrome patients)

258
Q

What percentage of Turner syndrome patients have Y chromosomes

259
Q

In Turner syndrome patients with a Y chrosome, what are the at higher risk of developing

A

Gonadal tumor aka gonadoblastoma

260
Q

What do Turner syndrome patients present with during infancy

A
  • edema of the dorsum of hand and foot (due to lymph stasis)

- Swelling of the nape of neck (due to cystic hygroma)

261
Q

What is the rate of heart issues with Turner syndrome pts

A
  • 25 to 50% develop congenital heart defects (left CV abnormalities, predictable coarction of aorta and bicuspid)
  • Most cause of increased mortality in children
262
Q

What is the single most important cause of amenorrhea

A

Turner syndrome

263
Q

What is the correlation of hypothyroid and Turner syndrome

A

50% develop Abs to thyroid, leading to hypothyroidism

264
Q

What is Turner syndrome assoacited with metabolically

A

-GLucose intolerance, obesity, insulin resistance

265
Q

What is the importance of insulin resistance seen in pts with Turner syndrome

A

Growth hormone that is given to pts with Turner syndrome will worsens the insulin resistance

266
Q

What are the physical characteristics seen in Turner syndrome pts

A
  • 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
Q

Is Turner syndrome assoacited with maternal or paternal X chromosomes

A

Paternal, as the lone X is maternal in 75% or patients

268
Q

What is the level of ovum in Turner syndrome

A

Fetal ovaries develop normally, but lack of second X leads to loss of oocytes, completed by year 2( menopause before menarche)

269
Q

What are the genes involved in Turner syndrome and where are they located

A

Short stature homeobox (SHOX) gene at Xp22.33

Robbins Pathology MOD1 (Chptr 1-6) (10 decks)

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