Pathology 5 (Genetic Disorders)

Front 1

how much of the human genome encodes proteins?

Back 1

less than two percent

25,000 genes that can give rise to more than 100,000 proteins via alternative splicing

Front 2

define genomics

Back 2

study of all the genes in the genome and their interactions

Front 3

how much DNA is shared between any two individuals?

Back 3

more than 99.5%

diversity in humans is encoded in less than 0.5% of DNA

Front 4

what are the two most common forms of DNA variations in the human genome?

Back 4

single-nucleotide polymorphisms (SNPs)

copy number variations (CNVs)

Front 5

what are SNPs?

Back 5

single-nucleotide polymorphisms

variation of a single isolated nucleotide position - almost always biallelic

Front 6

how do SNPs related to disease?

Back 6

could alter the gene product and predispose to the disease

more commonly, SNPs are just a marker that is co-inherited with a disease-associated gene as a result of physical proximity

Front 7

define linkage disequilibrium

Back 7

the non-random association of alleles at two or more loci

Front 8

what are CNVs?

Back 8

copy number variations

form of genetic variation consisting of different numbers of large contiguous stretches of DNA from 1000 base pairs to millions of base pairs

Front 9

define epigenetics

Back 9

heritable changes in gene expression that are not caused by alterations in DNA sequence

involved in tissue-specific expression of genes and genomic imprinting

Front 10

define proteomics

Back 10

the study and measurement of all proteins expressed in a cell or tissue

Front 11

what are miRNAs?

Back 11

micro RNAs

small RNA molecules that do not encode proteins, but instead inhibit gene expression after transcription

Front 12

how are mature miRNA molecules produced?

Back 12

transcribed to produce primary miRNA transcripts, which are then processed in the nucleus to form pre-miRNA

pre-miRNA is transported to the cytoplasm via specific transporter proteins, where Dicer generates mature miRNAs

Front 13

what cytoplasmic enzyme is responsible for cleaving pre-miRNA to form mature miRNA?

Back 13

Dicer

Front 14

what is the function of Dicer?

Back 14

Dicer is a cytoplasmic enzyme that is responsible for cleaving pre-miRNA to form mature miRNA

Front 15

into what multiprotein complex is mature, single-stranded miRNA incorporated? what does this complex do?

Back 15

RNA-induced silencing complex (RISC)

base-pairing between the complexed miRNA and its target mRNA directs the RISC to either cause mRNA cleavage or repress its translation

Front 16

what is RISC?

Back 16

RNA-induced silencing complex

multiprotein complex that complexes with miRNA and, via base-pairing between the miRNA strand and its target mRNA, either cleaves mRNA or represses its translation

Front 17

how many genes can be silenced by a single miRNA molecule?

Back 17

a single miRNA molecule can silence many target genes

Front 18

what are siRNAs?

Back 18

small interfering RNAs

synthetic miRNAs - behave identically to miRNAs except that by definition they must have been introduced into the cell by researchers/investigators

Front 19

what is the estimated lifetime frequency of genetic diseases?

Back 19

670 per 1000

Front 20

what are mendelian disorders?

Back 20

disorders related to mutations in a single gene that has large effects

Front 21

from what do chromosomal disorders arise?

Back 21

structural or numerical alteration in the autosomes and sex chromosomes

Front 22

from what do complex multigenic disorders arise?

Back 22

interactions between multiple variant forms of genes and environmental factors

only when several polymorphisms are present in an individual does disease occur

Front 23

what is GWAS?

Back 23

genome wide association studies

systematic method of identifying disease-associated polymorphisms

Front 24

define mutation

Back 24

a permanent change in the DNA

Front 25

what is the difference between mutations in germ cells vs. mutations in somatic cells?

Back 25

in germ cells, mutations are transmitted to progeny and thus lead to inherited disease

in somatic cells, mutations are not transmitted to progeny, but instead cause cancers and congenital malformations

Front 26

define point mutation

Back 26

a single nucleotide base is substituted by a different base

Front 27

define frameshift mutations

Back 27

insertion or deletion of one or two base pairs (importantly not a multiple of 3) from the DNA leading to alterations in the reading frame of the DNA strand

Front 28

what is a missense mutation?

Back 28

mutation that leads to the replacement of one amino acid by another

changes the meaning of the sequence of encoded protein

Front 29

what is a conservative missense mutation?

Back 29

substitution of one amino acid by another, where the substituted amino acid has little effect on the function of the protein

Front 30

what is a nonconservative missense mutation?

Back 30

substitution of one amino acid by another, where the substituted amino acid is very different from the original one and therefore has large effects on the function of the protein

Front 31

what is a nonsense mutation?

Back 31

a point mutation that changes an amino acid codon to a chain terminator (stop) codon

Front 32

what are trinucleotide-repeat mutations?

Back 32

amplification of a sequence of three nucleotides

although the specific nucleotide sequence varies between disorders, almost all affected sequences are some combination of guanine (G) and cytosine (C)

Front 33

aside from the amplification of a specific nucleotide sequence, what is the other distinguishing feature of trinucleotide-repeat mutation?

Back 33

they are dynamic (i.e. the degree of amplification increases during gametogenesis)

Front 34

what single-gene disorders have nonclassic patterns of inheritance?

Back 34

disorders resulting from:
- triplet repeat mutations
- mutations in mitochondrial DNA
- transmission influenced by genomic imprinting or gonadal mosaicism

Front 35

what is a hereditary disorder?

Back 35

disorder derived from one's parents and transmitted in the germ line through the generations

aka familial disorder

Front 36

define congenital

Back 36

means born with

Front 37

what is sickle cell trait?

Back 37

in an individual with heterozygous for the mutant (HbS) gene, only a proportion of the hemoglobin is HbS (the remainder being the normal HbA)

red cell sickling occurs in this situation only when there is exposure to lowered oxygen tension

Front 38

what is codominance?

Back 38

condition in which both alleles of a gene pair contribute to the phenotype seen

e.g. histocompatibility and blood group antigens

Front 39

what is pleiotropism?

Back 39

a single mutant gene leading to many end effects

Front 40

what is genetic heterogeneity?

Back 40

mutations at several genetic loci produce the same trait

Front 41

what are autosomal dominant disorders?

Back 41

disorder is manifested even in persons with the heterozygous genotype

Front 42

in the proportion of patients, afflicted with an autosomal dominant disorder, whose parents are not afflicted with the disorder, how did they inherit it?

Back 42

new mutations involving either the egg or sperm from which they were derived

Front 43

what is incomplete penetrance?

Back 43

individual inherits an autosomal dominant mutant gene, but they are phenotypically normal

Front 44

what is variable expressivity?

Back 44

a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals

Front 45

what are the two major categories of nonenzyme proteins affected in autosomal dominant disorders?

Back 45

those involved in regulation of complex metabolic pathways that are subject to feedback inhibition

key structural proteins

Front 46

what is dominant negative?

Back 46

mutant allele that impairs the function of a normal allele

Front 47

what are gain-of-function mutations?

Back 47

gene mutation in which the protein product of the mutant allele acquires new properties not normally associated with the wild-type protein

transmission of disorders produced by gain-of-function mutations is almost always autosomal dominant

Front 48

what nervous system disorders are autosomal dominant?

Back 48

huntington disease
neurofibromatosis
myotonic dystrophy
tuberous sclerosis

Front 49

what urinary disorders follow autosomal dominant inheritance?

Back 49

polycystic kidney disease

Front 50

what gastrointestinal disorders follow autosomal dominant inheritance?

Back 50

familial polyposis coli

Front 51

what hematopoietic disorders follow autosomal dominant inheritance?

Back 51

hereditary spherocytosis
von Willebrand disease

Front 52

what skeletal disorders follow autosomal dominant inheritance?

Back 52

marfan syndrome
ehlers-danlos syndrome (some variants)
osteogenesis imperfecta
achondroplasia

Front 53

what metabolic disorders follow autosomal dominant inheritance?

Back 53

familial hypercholesterolemia
acute intermittent porphyria

Front 54

what are autosomal recessive disorders?

Back 54

disorders which result only when both alleles at a given gene locus are mutated

Front 55

what are the features that characterize autosomal recessive disorders?

Back 55

trait does not usually affect the parents of the affected individual, but siblings may show the disease

siblings have one chance in four of having the trait

if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual is the product of a consanguineous marriage

Front 56

what type of inheritance pattern is followed by disorders resulting in mutated enzymes?

Back 56

autosomal recessive

Front 57

what metabolic diseases follow an autosomal recessive inheritance pattern?

Back 57

cystic fibrosis
phenylketonuria
galactosemia
homocystinuria
lysosomal storage diseases
alpha1-antitrypsin deficiency
wilson disease
hemochromatosis
glycogen storage diseases

Front 58

what hematopoietic diseases follow an autosomal recessive inheritance pattern?

Back 58

sickle cell anemia
thalassemias

Front 59

what endocrine diseases follow an autosomal recessive inheritance pattern?

Back 59

congenital adrenal hyperplasia

Front 60

what skeletal diseases follow an autosomal recessive inheritance pattern?

Back 60

ehlers-danlos syndrome (some variants)
alkaptonuria

Front 61

what nervous system diseases follow an autosomal recessive inheritance pattern?

Back 61

neurogenic muscular atrophies
friedreich ataxia
spinal muscular atrophy

Front 62

what inheritance pattern is followed by all sex-linked disorders?

Back 62

all sex-linked disorders are X-linked and almost all are recessive

Front 63

what is meant by the term hemizygous? where does it apply?

Back 63

an individual who has only one member of a chromosome pair or chromosome segment rather than the usual two; refers in particular to X-linked genes in males who under usual circumstances have only one X chromosome

males are said to be hemizygous for X-linked mutant genes because mutant genes on the X do not have corresponding alleles on the Y

Front 64

how are X-linked disorders carried to the children of an affected man?

Back 64

the affected male cannot transmit the disorder to his sons, but all of his daughters will be carriers

Front 65

what musculoskeletal disorders are transferred by an autosomal dominant inheritance pattern?

Back 65

duchenne muscular dystrophy

Front 66

what blood disorders are transferred by an autosomal dominant inheritance pattern?

Back 66

hemophilia A and B
chronic granulomatous disease
G6P dehydrogenase deficiency

Front 67

what immune disorders are transferred by an autosomal dominant inheritance pattern?

Back 67

agammaglobulinemia
wiskott-aldrich syndrome

Front 68

what metabolic disorders are transferred by an autosomal dominant inheritance pattern?

Back 68

diabetes insipidus
lesch-nyhan syndrome

Front 69

what nervous system disorders are transferred by an autosomal dominant inheritance pattern?

Back 69

fragile-X syndrome

Front 70

what enzyme is deficient in phenylketonuria?

Back 70

phenylalanine hydroxylase

Front 71

what enzyme is deficient in tay-sachs disease?

Back 71

hexosaminidase A (alpha subunit)

Front 72

what enzyme is deficient in severe combined immunodeficiency?

Back 72

adenosine deaminase

Front 73

what is caused by alpha1-antitrypsin deficiency?

Back 73

emphysema
liver disease

Front 74

what protein is deficient in familial hypercholesterolemia?

Back 74

low-density lipoprotein receptor

Front 75

what protein is deficient in vitamin D-resistant rickets?

Back 75

vitamin D receptor

Front 76

what protein is deficient in alpha-thalassemia?

Back 76

hemoglobin

Front 77

what protein is deficient in beta-thalassemia?

Back 77

hemoglobin

Front 78

what protein is deficient in sickle cell anemia?

Back 78

hemoglobin

Front 79

what protein is deficient in osteogenesis imperfecta?

Back 79

collagen

Front 80

what protein is deficient in ehlers-danlos syndromes?

Back 80

collagen

Front 81

what protein is deficient in marfan syndrome?

Back 81

fibrillin-1

Front 82

what protein is deficient in duchenne/becker muscular dystrophy?

Back 82

dystrophin

Front 83

what protein is deficient in hereditary spherocytosis?

Back 83

spectrin

Front 84

what protein is deficient in hemophilia A?

Back 84

factor VIII

Front 85

what protein is deficient in hereditary retinoblastoma?

Back 85

Rb protein

Front 86

what protein is deficient in neurofibromatosis type I?

Back 86

neurofibromin

Front 87

what is the estimated prevalence of Marfan syndrome?

Back 87

1 in 5000

Front 88

what type of inheritance pattern is displayed by Marfan syndrome?

Back 88

autosomal dominant inheritance

Front 89

what is the major component of microfibrils found in the extracellular matrix?

Back 89

fibrillin

Front 90

what is the purpose of fibrillin?

Back 90

it is the major component of microfibrils found in the extracellular matrix, which provide a scaffolding on which tropoelastin is deposited to form elastic fibers

Front 91

where are microfibrils particularly abundant?

Back 91

widely distributed in the body, but particularly abundant in the aorta, ligaments, and the ciliary zonules that support the lens

Front 92

what disorder is caused by a mutation in the FBN1 gene?

Back 92

inherited defect in the extracellular glycoprotein called fibrillin-1

marfan syndrome

Front 93

what disorder is caused by a mutation in the FBN2 gene?

Back 93

congenital contractural arachnodactyly

Front 94

what is the effect of a loss of microfibrils on TGF-beta?

Back 94

leads to abnormal and excessive activation of TGF-beta, since normal microfibrils sequester TGF-beta and thus control the bioavailability of this cytokine

Front 95

what is the effect of excessive TGF-beta signalling in Marfan syndrome?

Back 95

has delerious effects on vascular smooth muscle development and the integrity of extracellular matrix

Front 96

what are the skeletal abnormalities associated with Marfan syndrome?

Back 96

unusually tall with exceptionally long extremities and long, tapering fingers and toes

joint ligaments in the hands and feet are lax (double jointed)

the head is typically dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges

spinal deformities (kyphosis, scoliosis, or rotation/slipping of dorsal/lumbar vertebrae)

pectus excavatum (deeply depressed sternum)
pigeon-breast deformity

Front 97

what are the ocular changes associated with Marfan syndrome?

Back 97

ectopia lentis - bilateral subluxation or dislocation (usually outward and upward) of the lens

Front 98

what is ectopia lentis?

Back 98

displacement or malposition of the eye's crystalline lens from its normal location

Front 99

on finding bilateral ectopia lentis, what disorder should be suspected?

Back 99

Marfan syndrome

Front 100

what are the two most common cardiovascular lesions in Marfan syndrome?

Back 100

mitral valve prolapse

dilation of the ascending aorta due to cystic medionecrosis

aortic incompetence

Front 101

what is the effect of weakening the aortic media in Marfans syndrome?

Back 101

predisposes to an intimal tear, which may initiate an intramural hematoma that cleaves the layers of the media to produce aortic dissection

Front 102

what are the requirements for clinical diagnosis of Marfans syndrome?

Back 102

must be based on major involvement of two out of four organ systems (skeletal, cardiovascular, ocular, and skin) as well as minor involvement of another organ

Front 103

what are Ehlers-Danlos syndromes?

Back 103

clinically and genetically heterogeneous group of disorders that result from some defect in the synthesis or structure of fibrillar collagen

Front 104

what happens to skin in Ehlers-Danlos syndrome?

Back 104

becomes hyperextensible

extraordinarily stretchable, extremely fragile, and vulnerable to trauma

Front 105

what happens to joints in Ehlers-Danlos syndrome?

Back 105

become hypermobile

predisposition to joint dislocation

Front 106

what are the serious internal complications of Ehlers-Danlos syndrome?

Back 106

rupture of the colon and large arteries (vascular type)

ocular fragility with rupture of cornea and retinal detachment (kyphoscoliosis type)

diaphragmatic hernia (classical type)

Front 107

what are the three important types of Ehlers-Danlos syndrome? what are their causes?

Back 107

classical (I/II) - mutations in genes of type V collagen

vascular (IV) - abnormalities of type 3 collagen

kyphoscoliosis (VI) - deficiency of lysyl hydroxylase

Front 108

what is the defect in kyphoscoliosis type (type VI) Ehlers-Danlos syndrome?

Back 108

deficiency of lysyl hydroxylase

Front 109

what is the defect in vascular type (type IV) Ehlers-Danlos syndrome?

Back 109

abnormalities in type III collagen

Front 110

what is the defect in classical type (type I/II) Ehlers-Danlos syndrome?

Back 110

abnormalities in type V collagen

Front 111

what is the most common autosomal recessive form of Ehlers-Danlos syndrome?

Back 111

kyphoscoliosis type (type VI)

Front 112

what type of collagen is rich in blood vessels and intestines?

Back 112

type III collagen

Front 113

what is the fundamental defect in the arthrochalasia type of Ehlers-Danlos syndrome?

Back 113

conversion of type I procollagen to collagen

Front 114

what is the fundamental defect in the dermatosparaxis type of Ehlers-Danlos syndrome?

Back 114

conversion of type I procollagen to collagen

Front 115

in what gene is the mutation found in familial hypercholesterolemia?

Back 115

gene encoding the receptor for LDL (involved in the transport and metabolism of cholesterol)

Front 116

how highly elevated are the plasma cholesterol levels in familial hypercholesterolemia heterozygotes?

Back 116

two-fold to three-fold

leads to tendinous xanthomas and premature atherosclerosis in adult life

Front 117

how highly elevated are the plasma cholesterol levels in familial hypercholesterolemia homozygotes?

Back 117

five-fold to six-fold

leads to skin xanthomas, and coronary, cerebral, and peripheral vascular atherosclerosis at an early age

myocardial infarction may develop before age 20

Front 118

how much of the body's cholesterol circulates in the plasma?

Back 118

7% in the form of LDL

Front 119

what are the the lipid components of VLDL particles?

Back 119

rich in triglycerides

lesser amounts of cholesteryl esters

Front 120

what happens to VLDL particles when they reach capillaries of adipose tissue or muscle?

Back 120

it is cleaved by lipoprotein lipase, a process that extracts most of the triglycerides

Front 121

what results from the removal of triglycerides from VLDLs?

Back 121

intermediate-density lipoprotein (IDL) particles

reduced in triglycerides
enriched in cholesteryl esters

Front 122

what two apoproteins are in both VLDLs and IDLs?

Back 122

apoB-100
apoE

Front 123

what happens to newly formed IDL particles?

Back 123

approximately 50% is rapidly taken up by the liver by receptor-mediated transport

remaining IDL is subjected to further metabolic processing that removes most of the remaining triglycerides and apoprotein E, yielding cholesterol-rich LDL particles

Front 124

what molecules are recognized by the LDL receptor?

Back 124

apoprotein B-100 and apoprotein E

two molecules contained in IDLs

Front 125

how are cholesterol-rich LDL particles formed?

Back 125

metabolism of IDL particles that removes most of the remaining triglycerides and apoprotein E

Front 126

what is the immediate and major source of plasma LDL?

Back 126

IDL

Front 127

what are the two mechanisms for removal of LDL from plasma?

Back 127

LDL receptor on liver cells

scavenger receptor to pick up oxidized LDL

Front 128

how do LDL surface receptors mediate LDL clearance?

Back 128

LDL binds to cell surface receptors, which are clustered in coated pits

pits containing the receptor-bound LDL are internalized by invagination to form coated vesicles

vesicles migrate with the cell to fuse with the lysosomes

LDL dissociates from the receptor, which is recycled to the surface

apoproteins are hydrolyzed to amino acids, whereas the cholesteryl esters are broken down to free cholesterol

Front 129

what proteins are required for the exit of cholesterol from lysosomes?

Back 129

NPC1
NPC2

Front 130

what processes are affected by the release of intracellular cholesterol?

Back 130

cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of HMG CoA reductase

cholesterol activates the enzyme acyl-coenzyme A: cholesterol acyltransferase, favoring esterification and storage of excess cholesterol

cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation of cholesterol

Front 131

what is the rate limiting enzyme in the synthetic pathway of cholesterol?

Back 131

HMG CoA reductase

3-hydroxy-3-methylglutaryl coenzyme A reductase

Front 132

what cells have scavenger receptors for chemically altered (acetylated or oxidized) LDL?

Back 132

monocytes
macrophages

Front 133

what is the cause of the appearance of xanthomas and premature atherosclerosis?

Back 133

in the face of hypercholesterolemia, there is a marked increase in the scavenger receptor-mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and the vascular wall

Front 134

what is a xanthoma?

Back 134

build up of certain fats underneath the surface of the skin

Front 135

what are the two special properties of the hydrolytic enzymes in lysosomes?

Back 135

1) function in the acidic milieu of the lysosomes

2) constitute a special category of secretory proteins that are destined not for the extracellular fluids but for intracellular organelles

Front 136

what happens in the Golgi apparatus to lysosomal enzymes?

Back 136

undergo a variety of post-translational modifications, including the attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains

Front 137

what is the function of the terminal mannose-6-phosphate groups on lysosomal enzymes?

Back 137

act as an "address label" that is recognized by specific receptors on the inner surface of the Golgi membrane to insert the lysosomal enzymes into the Golgi membrane

Front 138

what are the three general approaches to the treatment of lysosomal storage diseases?

Back 138

enzyme replacement therapy

substrate reduction therapy

exogenous competitive inhibitor of the enzyme (paradoxically binds to the mutant enzyme and act as the folding template to assist in proper folding of enzyme)

Front 139

what is molecular chaperone therapy?

Back 139

use of an exogenous competitive inhibitor of the enzyme (acts as a folding template to assist in proper folding of the lysosomal enzyme)

Front 140

what are GM2 gangliosidoses?

Back 140

group of three lysosomal storage disorders caused by an inability to catabolize GM2 gangliosides

Front 141

what is required for degradation of GM2 gangliosides?

Back 141

three polypeptides encoded by three distinct genes

Front 142

what is the most common form of GM2 gangliosidosis?

Back 142

Tay-Sachs disease

deficiency of hexosaminidase A (alpha subunit)

Front 143

what is the primary defect in Tay-Sachs disease?

Back 143

severe deficiency of hexosaminidase A (alpha subunit)

Front 144

in what population is Tay-Sachs disease especially prevalent?

Back 144

Ashkenazic Jews

Front 145

in what tissues do GM2 gangliosides accumulate?

Back 145

heart
liver
spleen
neurons
retina

Front 146

involvement of what organs dominates the clinical picture in Tay-Sachs disease?

Back 146

neurons in the CNS and ANS
retina

Front 147

how do neurons in Tay Sachs disease look on microscopic examination?

Back 147

ballooned with cytoplasmic vacuoles, each representing a markedly distended lysosome filled with gangliosides

Front 148

what stains for fat are positive in Tay-Sachs disease?

Back 148

oil red O
Sudan Black B

Front 149

what are the most prominent types of cytoplasmic inclusions in Tay Sachs disease?

Back 149

whorled configurations within lysosomes composed of onion-skin layers of membranes

seen via electron microscope

Front 150

what is the characteristic finding in the eyes of a patient with Tay Sachs disease?

Back 150

cherry red spot in the macula

represents the accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina

Front 151

what is the cause of the cherry red spot in the eye of patients with Tay Sachs disease?

Back 151

represents the accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina

Front 152

when do clinical features of Tay Sachs disease manifest?

Back 152

affected infants seem normal at birth, but begin to manifest signs and symptoms at about age 6 months

Front 153

what are the presenting symptoms of Tay Sachs disease?

Back 153

motor and mental deterioration

motor incoordination

mental obtundation leading to muscular flaccidity, blindness, and increasing dementia

cherry red spot in macula

complete vegetative state at 1-2 yrs
death at 2-3 yrs

Front 154

what is the effect of most of the mutations that cause Tay Sachs disease?

Back 154

most affect protein folding

Front 155

what is the potential treatment type for Tay-Sachs disease?

Back 155

chaperone therapy

Front 156

how can antenatal diagnosis and carrier detection of Tay-Sachs disease be performed?

Back 156

enzyme assays
DNA-based analysis

Front 157

what is the major defect in Sandhoff disease?

Back 157

beta-subunit defect of hexosaminidase A

Front 158

what are the three types of GM2 gangliosidoses?

Back 158

Tay-Sachs (hexosaminidase A, alpha subunit)

Sandhoff disease (hexosaminidase A, beta subunit)

GM2 activator deficiency

Front 159

what is accumulated in the lysosomes in Niemann-Pick Disease, Types A and B?

Back 159

sphingomyelin

Front 160

what is the deficiency in Niemann-Pick Disease, Types A and B?

Back 160

sphingomyelinase

Front 161

what is the difference between Niemann-Pick Disease, Types A and B?

Back 161

type A is a severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, progressive wasting, and early death (in the first 3 years of life)

type B is a less severe form in which patients have organomegaly but generally no CNS involvement

Front 162

in what population is Niemann-Pick disease predominant?

Back 162

Ashkenazi Jews

Front 163

how is the sphingomyelinase gene expressed?

Back 163

preferentially expressed from the maternal chromosome as a result of epigenetic silencing of the paternal gene

Front 164

what is seen in the vacuoles found in Niemann-Pick, types A and B?

Back 164

secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures, sometimes called "zebra" bodies

Front 165

where are the lipid-laden phagocytic foam cells distributed?

Back 165

spleen
liver
lymph nodes
bone marrow
tonsils
GI tract
lungs

Front 166

what is the effect of splenic involvement in Niemann-Pick disease, types A and B?

Back 166

generally produces massive enlargement

Front 167

what is the effect on the brain in Niemann-Pick disease, types A and B?

Back 167

gyri are shrunken
sulci are widened

Front 168

what is the dominant histologic change in Niemann-Pick disease?

Back 168

vacuolation and ballooning of neurons

Front 169

when do the clinical manifestations of type A Niemann-Pick disease present?

Back 169

may be present at birth and almost invariably become evident by age 6 months

Front 170

what are the symptoms/presentations of Niemann-Pick disease,types A and B?

Back 170

progressive failure to thrive
vomiting
fever
generalized lymphadenopathy
progressive deterioration of psychomotor function
death (usually within the first/second year of life)

Front 171

what is the most common type of Niemann-Pick disease?

Back 171

Niemann-Pick disease, type C

more common than types A and B together

Front 172

mutations of what two genes can give rise to Niemann-Pick disease, type C?

Back 172

NPC1
NPC2

Front 173

what is the defect in Niemann-Pick disease, type C?

Back 173

primary defect in lipid transport

Front 174

what are NPC1 and NPC2 involved in?

Back 174

transport of free cholesterol from the lysosomes to the cytoplasm

Front 175

what are the possible clinical presentations of Niemann-Pick disease, type C?

Back 175

hydrops fetalis (stillbirth)

neonatal hepatitis

chronic form characterized by progressive neurologic damage

Front 176

how does the most common form of type C Niemann-Pick disease present?

Back 176

ataxia
vertical supranuclear gaze palsy
dystonia
dysarthria
psychomotor regression

Front 177

what is the inheritance pattern of Gaucher Disease?

Back 177

autosomal recessive inheritance

Front 178

what is the defect in Gaucher Disease?

Back 178

mutation encoding glucocerebrosidase enzyme

normally cleaves the glucose residue from ceramide

Front 179

what is the most common lysosomal storage disorder?

Back 179

Gaucher Disease

Front 180

what is the function of glucocerebrosidase?

Back 180

cleaves the glucose residue from ceramide

Front 181

what product accumulates in lysosomes in Gaucher Disease?

Back 181

glucocerebrosides

Front 182

what are the primary cells that glucocerebrosides accumulate in in patients with Gaucher Disease?

Back 182

principally in phagocytes

some subtypes in the central nervous system

Front 183

from what metabolic process is glucocerebroside formed?

Back 183

continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes

Front 184

what are the causes of pathologic changes in Gaucher disease?

Back 184

burden of storage material

activation of macrophages and the consequent secretion of cytokines (IL-1, IL-6, TNF)

Front 185

what is the most common clinical subtype of Gaucher disease?

Back 185

type I (chronic, non-neuronopathic form)

storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain (splenic and skeletal involvements dominate this pattern of the disease)

Front 186

in what population is Gaucher disease most common?

Back 186

type I - Jewish people of European stock

type II - no predilection for Jews

Front 187

what is type I Gaucher disease?

Back 187

(chronic, non-neuronopathic form)

storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain (splenic and skeletal involvements dominate this pattern of the disease)

Front 188

what is type II Gaucher disease?

Back 188

acute neuronopathic Gaucher disease

infantile acute cerebral pattern

virtually no glucocerebrosidase activity in the tissues

hepatosplenomegaly, but the clinical picture is dominated by progressive CNS involvement, leading to death at an early age

Front 189

what is type III Gaucher disease?

Back 189

intermediate between type I and type II

systemic involvement characteristic of type I with CNS disease that usually begins in adolescence or early adulthood

Front 190

what are Gaucher cells?

Back 190

phagocytic cells distended with glucocerebrosides found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer's patches in Gaucher disease

Front 191

describe the histologic appearance of Gaucher cells

Back 191

rarely appear vacuolated but instead have a fibrillary type of cytoplasm likened to crumpled tissue paper

often enlarged, with one or more dark, ccentrically placed nuclei

periodic acid-schiff staining is usually intensely positive

Front 192

what is seen in the distended lysosomes in Gaucher disease?

Back 192

stored glucocerebroside in stacks of bilayers

Front 193

when are Gaucher cells seen in the Virchow-Robin spaces?

Back 193

in Gaucher patients with cerebral involvement

arterioles are surrounded by swollen adventitial cells

no storage of lipids in neurons, but neurons appear shriveled and are progressively destroyed

Front 194

when do signs and symptoms of type I Gaucher disease appear?

Back 194

in adult life

related to splenomegaly or bone involvement

Front 195

what are the symptoms of type I Gaucher disease?

Back 195

pancytopenia or thrombocytopenia secondary to hypersplenism

pathologic bone fractures and bone pain (if there has been sufficient expansion of the marrow space)

Front 196

what is the mainstay treatment of Gaucher disease?

Back 196

replacement therapy with recombinant enzymes

Front 197

what are the mucopolysaccharidoses?

Back 197

group of closely related syndromes that result from genetically determined deficiencies of lysosomal enzymes involved in the degradation of mucopolysaccharides

Front 198

what are mucopolysaccharides?

Back 198

glycosaminoglycans

long-chain complex carbohydrates that are linked with proteins to form proteoglycans

Front 199

what glycosaminoglycans accumulate in mucopolysaccharidoses?

Back 199

dermatan sulfate
heparan sulfate
keratan sulfate
chondroitin sulfate

Front 200

what is the inheritance pattern of mucopolysaccharidoses?

Back 200

all except Hunter syndrome are inherited as autosomal recessive disorders

Hunter syndrome is an X-linked recessive trait

Front 201

in general, how are mucopolysaccharidoses characterized?

Back 201

coarse facial features
clouding of the cornea
joint stiffness
mental retardation

Front 202

in what types of cells are mucopolysaccharides accumulated?

Back 202

mononuclear phagocytes
endothelial cells
intimal smooth muscle cells
fibroblasts

Front 203

in what tissues are mucopolysaccharides accumulated?

Back 203

spleen
liver
bone marrow
lymph nodes
blood vessels
heart

Front 204

how do cells affected by mucopolysaccharide accumulation look microscopically?

Back 204

distended with apparent clearing of the cytoplasm to create "balloon cells"

Front 205

how do cells affected by mucopolysaccharide accumulation look in the electron microscope?

Back 205

clear cytoplasm can be resolved as numerous minute vacuoles

Front 206

what are the common symptoms of mucopolysaccharidoses?

Back 206

hepatosplenomegaly
skeletal deformities
valvular lesions
subendothelial arterial deposits (particularly in the coronary arteries)
lesions in the brain

myocardial infarction and cardiac decompensation

Front 207

what are the important causes of death in mucopolysaccharidoses?

Back 207

myocardial infarction

cardiac decompensation

Front 208

what is Hurler syndrome?

Back 208

aka mucopolysaccharidosis I-H

deficiency of alpha-1-iduronidase

Front 209

what is the deficiency in Hurler syndrome?

Back 209

alpha-1-iduronidase

Front 210

describe the clinical manifestations of Hurler syndrome

Back 210

affected infants appear normal at birth but develop hepatosplenomegaly by age 6-24 months

growth is retarded
develop coarse facial features
develop skeletal deformities

death occurs by age 6-10 years (CV complications)

Front 211

what is Hunter syndrome?

Back 211

mucopolysaccharidosis II

X-linked inheritance

absence of corneal clouding, and milder clinical course

Front 212

what is the inheritance pattern of Hurler syndrome?

Back 212

aka mucopolysaccharidosis type I-H

autosomal recessive inheritance

Front 213

what is the inheritance pattern of Hunter syndrome?

Back 213

aka mucopolysaccharidosis type II

X-linked inheritance

Front 214

what are glycogenoses?

Back 214

hereditary deficiencies of one of the enzymes involved in the synthesis or sequential degradation of glycogen

Front 215

what is the first step in glycogen synthesis?

Back 215

conversion of glucose to glucose-6-phosphate by the action of a hexokinase (glucokinase)

Front 216

what is the second step in glycogen synthesis?

Back 216

G6P -(phosphoglucomutase)-> G1P -> uridine diphosphoglucose

Front 217

what enzymes elongate the glycogen chain and branches?

Back 217

glycogen synthetases

Front 218

what are the major bonds between glucose molecules in glycogen particles?

Back 218

alpha-1,4-glucoside bonds

alpha-1,6-glucoside bonds (branch points)

Front 219

what enzymes in the liver and muscle split glucose-1-phosphate residues from glycogen?

Back 219

phosphorylases

leaves about four glucose residues on each branch of glycogen molecules

Front 220

what is limit dextrin?

Back 220

branched oligosaccharide that remains after phosphorylase cleaves glucose from the glycogen molecule

Front 221

what enzyme further degrades limit dextrin?

Back 221

debranching enzyme

Front 222

what is the enzyme that degrades glycogen in lysosomes?

Back 222

acid maltase

Front 223

what are hepatic forms of glycogenoses?

Back 223

inherited deficiency of hepatic enzymes that are involved in glycogen degradation

Sx:
storage of glycogen in liver
hypoglycemia

Front 224

what is von Gierke disease?

Back 224

aka type I glycogenosis

deficiency of glucose-6-phosphatase

hepatic glycogenosis

Front 225

what are the hepatic forms of glycogenoses?

Back 225

von Gierke disease
deficiency of liver phosphorylase
deficiency of debranching enzyme

Front 226

what dominates the clinical picture in von Gierke disease?

Back 226

hepatic enlargement
hypoglycemia

Front 227

what dominates the clinical picture in debranching enzyme deficiency?

Back 227

hepatic enlargement
hypoglycemia

Front 228

what are the symptoms of the myopathic forms of glycogenoses?

Back 228

muscle cramps after exercise

lactate levels in the blood fail to rise after exercise

Front 229

what is McArdle disease?

Back 229

aka type V glycogenosis

deficiency of muscle phosphorylase

Sx:
muscle cramps after exercise
serum lactate levels don't rise after exercise

Front 230

what are the myopathic forms of glycogenoses?

Back 230

McArdle disease (type V glycogenosis)

deficiency of muscle phosphofructokinase (type VII glycogenosis)

Front 231

with what is deficiency of alpha-glucosidase (acid maltase) associated?

Back 231

glycogen storage in many organs

death in early life

lysosomal storage of glycogen (acid maltase is a lysosomal enzyme)

Front 232

what is Pompe disease?

Back 232

type II glycogenosis

deficiency of alpha-glucosidase (acid maltase)

Sx:
glycogen storage in many organs
death in early life
cardiomegaly

Front 233

with what is deficiency of branching enzyme associated?

Back 233

glycogen storage in many organs

death in early life

Front 234

what was the first human inborn error of metabolism to be discovered?

Back 234

alkaptonuria (ochronosis)

autosomal recessive deficiency of homogentisic oxidase

Front 235

what is alkaptonuria?

Back 235

aka ochronosis

autosomal recessive deficiency of homogentisic oxidase

Sx:
degenerative arthropathy
(develops slowly, clinically evident in 30s)

not life-threatening, but severely crippling

Front 236

what is the function of homogentisic oxidase?

Back 236

converts homogentisic acid to methylacetoacetic acid in the tyrosine degradation pathway

Front 237

what is the effect of homogentisic acid accumulation in the body?

Back 237

happens in alkaptonuria

a large amount is excreted, imparting a black color to the urine if allowed to stand and undergo oxidation

binds to collagen in connective tissues, tendons, and cartilage, imparting to these tissues a blue-black pigmentation

Front 238

from what do the most serious consequences of ochronosis stem?

Back 238

deposits of the pigment in the articular cartilages of the joints

pigment accumulation causes the cartilage to lose its normal resiliency and become brittle and fibrillated

Front 239

what joints are attacked in alkaptonuria?

Back 239

particularly intervertebral discs

later the knees, shoulders, and hips may be affected

small joints of the hands and feet are usually spared

Front 240

what are the clinical features of alkaptonuria?

Back 240

degenerative arthropathy develops slowly and usually does not become clinically evident until the 30s

not life threatening, but may be severely crippling

Front 241

what two types of genes regulate the normal growth and differentiation of cells?

Back 241

proto-oncogenes (promotes cell growth)

tumor suppressor (restrains cell growth)

Front 242

what is the inheritance pattern of most familial cancers?

Back 242

autosomal dominant

Front 243

what normal phenotypic characteristics are governed by multifactorial inheritance?

Back 243

hair color
eye color
skin color
height
intelligence

Front 244

how many chromosomes are contained in human somatic cells?

Back 244

46 chromosomes

22 homologous pairs of autosomes
two sex chromosomes

Front 245

what is karyotyping?

Back 245

the study of chromosomes

Front 246

what is the usual procedure to examine chromosomes?

Back 246

arrest dividing cells in metaphase with mitotic spindle inhibitors (colcemid) and stain the chromosomes

Front 247

how are karyotypes obtained?

Back 247

arrange each pair of autosomes according to length, followed by the sex chromosomes

Front 248

what is G banding?

Back 248

using a Giemsa stain to ID individual chromosomes on the basis of a distinctive and reliable pattern of alternating light and dark bands

Front 249

which arm of a chromosome is designated p?

Back 249

short arm

(p is for petit)

Front 250

which arm of a chromosome is designated q?

Back 250

long arm

(short arm is p for petit, and q is the next letter in the alphabet)

Front 251

what is a euploid?

Back 251

any exact multiple of the haploid number

Front 252

what is aneuploidy?

Back 252

an error occurring in meiosis or mitosis in which a cell acquires a chromosome complement that is not an exact multiple of 23

Front 253

what are the usual causes for aneuploidy?

Back 253

nondisjunction

anaphase lag

Front 254

what is the result of nondisjunction in gametogenesis?

Back 254

gametes formed will have either an extra chromosome (n + 1) or one less chromosome (n - 1)

Front 255

what is anaphase lag?

Back 255

one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus

result is one normal cell and one cell with monosomy

Front 256

what generally happens when a monosomic zygote is formed?

Back 256

generally too much genetic information to permit live birth or even embryogenesis

(several autosomal trisomies do permit survival)

Front 257

what is the only trisomy that doesn't yield severely handicapped infants who almost invariably die at an early age?

Back 257

trisomy 21

Front 258

what is mosaicism?

Back 258

two or more populations of cells with different chromosomal complement in the same individual caused by mitotic errors in early development

Front 259

what type of mosaicism is most common?

Back 259

mosaicism of the sex chromosome

autosomal mosaicism is much less common

Front 260

what is the effect of an error in an early mitotic division affecting the autosomes?

Back 260

usually leads to a nonviable mosaic due to autosomal monosomy

Front 261

what usually causes structural changes in chromosomes?

Back 261

chromosome breakage followed by loss or rearrangement of material

(occurs spontaneously at a low rate that is increased by exposure to environmental mutagens)

Front 262

what is a ring chromosome?

Back 262

special form of deletion, produced when a break occurs at both ends of a chromosome with fusion of the damaged ends

Front 263

why do ring chromosmes usually cause serious consequences?

Back 263

they do not behave normally in meiosis or mitosis

Front 264

what is an inversion?

Back 264

a rearrangement that involves two breaks within a single chromosome with reincorporation of the inverted, intervening segment

Front 265

what is a paracentric inversion?

Back 265

an inversion involving only one arm of the chromosome

Front 266

what is a pericentric inversion?

Back 266

an inversion with breaks on opposite sides of the centromere

Front 267

what is an isochromosome?

Back 267

chromosome consisting of either two short arms or two long arms only

formed when one arm is lost and the remaining arm is duplicated

Front 268

what is a translocation?

Back 268

a segment of one chromosome is transferred to another

Front 269

what is a balanced reciprocal translocation?

Back 269

single breaks in each of two chromosomes, with exchange of material

Front 270

what is a robertsonian translocation?

Back 270

aka centric fusion

a translocation between two acrocentric chromosomes, leading two one very large chromosome and one extremely small one

(the breaks typically occur close to the centromeres of each chromosome)

Front 271

what is the most common of the chromosomal disorders?

Back 271

trisomy 21

Down Syndrome

Front 272

what is the cause of Down Syndrome?

Back 272

trisomy 21

Front 273

what is the incidence of trisomy 21 in newborns in the US?

Back 273

1 in 700 newborns

Front 274

what is the most common cause of trisomy?

Back 274

meiotic nondisjunction

Front 275

what factor has a strong influence on the incidence of trisomy 21?

Back 275

maternal age

1 / 1550 live births in mothers <20
1 / 25 live births in mothers >45

Front 276

where does meiotic nondisjunction of chromosome 21 occur in most cases of down syndrome (trisomy 21)?

Back 276

ovum

strong influence of maternal age on incidence of trisomy 21

Front 277

how often does the extrachromosomal meterial in Down syndrome derive from the presence of a robertsonian translocation of the long arm of chormosome 21 to another acrocentric chromosome?

Back 277

4% of cases

Front 278

how often does Down syndrome result from mosaicism caused by mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis?

Back 278

1% of cases

Front 279

what are the diagnostic clinical features of Down syndrome (trisomy 21)?

Back 279

flat facial profile
oblique palpebral fissures
epicanthic folds

also see:
mental retardation
abundant neck skin
congenital heart defects
intestinal stenosis
simian crease
umbilical hernia
predisposition to leukemia
hypotonia
gap btwn first and second toe

Front 280

what is the IQ range for 80% of patients with Down syndrome?

Back 280

25 - 50

Front 281

how many Down syndrome patients have congenital heart disease?

Back 281

40%

Front 282

what are the most common congenital heart defects in Down syndrome patients?

Back 282

ostium primum
atrial septal defects
atrioventricular valve malformations
ventricular septal defects

Front 283

what congenital malformations are common in Down syndrome?

Back 283

congenital heart defects
esophageal atresia
small bowel atresia

Front 284

how much is the risk of developing acute leukemia increased in children with Down syndrome (trisomy 21)?

Back 284

10- to 20-fold increased risk of both acute lymphoblastic leukemias and acute myeloid leukemias

Front 285

what occurs in virtually all patients with Down syndrome (trisomy 21) older than age 40?

Back 285

neuropathologic changes characteristic of Alzheimer disease

Front 286

what is the effect of abnormal immune responses in patients with Down syndrome?

Back 286

predisposition to serious infections, especially of the lungs

predisposition to thyroid autoimmunity

Front 287

what is the cause of Edwards syndrome?

Back 287

trisomy 18

extra copy of chromosome 18

Front 288

what is the cause of patau syndrome?

Back 288

trisomy 13

extra copy of chromosome 13

Front 289

what happens in most cases of trisomy 18 and trisomy 13?

Back 289

trisomy 13 - Patau syndrome
trisomy 18 - Edwards syndrome

most succumb within a few weeks to months (rarely do these infants survive beyond the first year of life)

Front 290

what are the symptoms of Edwards syndrome (trisomy 18)?

Back 290

prominent occiput
mental retardation
low set ears
micrognathia
short neck
overlapping fingers
congenital heart defects
renal malformations
limited hip abduction
rocker-bottom feet

Front 291

what is the incidence of trisomy 18 (Edwards syndrome)?

Back 291

1 in 8000 births

Front 292

what are the symptoms of Patau syndrome (trisomy 13)?

Back 292

microcephaly
mental retardation
microphthalmia
cleft lip and palate
polydactyly
cardiac defects
umbilical hernia
renal defects
rocker-bottom feet

Front 293

what is the incidence of trisomy 13 (Patau syndrome)?

Back 293

1 in 15,000 births

Front 294

what is the incidence of chromosome 22q11.2 deletion syndrome?

Back 294

1 in 4000 births

often missed because of variable clinical features

Front 295

what are the clinical features of chromosome 22q11.2 deletion syndrome?

Back 295

congenital heart defects
abnormalities of the palate
facial dysmorphism
developmental delay
variable degrees of T-cell immunodeficiency
variable degrees of hypocalcemia

Front 296

what two different disorders were previously considered to encompass the clinical features of chromosome 22q11.2 deletion syndrome?

Back 296

DiGeorge syndrome

velocardiofacial syndrome

Front 297

for what type of illnesses are 22q11.2 deletion syndrome patients at particularly high risk?

Back 297

psychotic illnesses
- schizophrenia
- bipolar disorders

attention deficit hyperactivity disorder

Front 298

what is X-inactivation?

Back 298

silencing of one of the X chromosomes in women that occurs at random among all cells in the blastocyst around day 16 of embryonic life

Front 299

how can an inactive X chromosome be seen?

Back 299

in the interphase nucleus

darkly staining small mass in contact with the nuclear membrane (Barr body)

Front 300

given X inactivation during embryogenesis, how are gametes produced in the ovaries?

Back 300

the one X chromosome that is inactivated during embryogenesis is selectively reactivated in oogonia before the first meiotic division

Front 301

what is necessary to determine the male sex?

Back 301

regardless of the number of X chromosomes, the presence of a single Y determines the male sex

Front 302

what is SRY?

Back 302

sex-determining region of Y gene

gene that dictates testicular development located on the distal short arm of the Y chromosome

Front 303

what are the features that are common to all sex chromosome disorders?

Back 303

cause subtle, chronic problems relating to sexual development and fertility

often difficult to diagnose at birth (many first recognized at puberty)

the higher the number of X chromosomes, the greater the likelihood of mental retardation

Front 304

what is Klinefelter syndrome?

Back 304

XXY

male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes

Front 305

what is the incidence of Klinefelter syndrome (XXY)?

Back 305

1 in 660 live male births

Front 306

what are the symptoms of Klinefelter syndrome (XXY)?

Back 306

long legs which create the appearance of an elongated body

small atrophic testes
small penis
lack of deep voice
lack of beard
lack of pubic hair
gynecomastia

Front 307

what metabolic problems are commonly seen in Klinefelter syndrome (XXY)?

Back 307

type 2 diabetes
metabolic syndrome

Front 308

what cardiovascular defect is common in patients with Klinefelter syndrome (XXY)?

Back 308

mitral valve prolapse

Front 309

what are the important hormone levels in patients with Klinefelter syndrome (XXY)?

Back 309

elevated FSH
elevated LH
low testosterone
elevated estradiol

Front 310

why does Klinefelter syndrome (XXY) cause reduced spermatogenesis and male infertility?

Back 310

testicular tubules are totally atrophied and replaced by pink, hyaline, collagenous ghosts
OR
apparently normal testicular tubules are interspersed with atrophic tubules

Front 311

how do Leydig cells appear in Klinefelter syndrome (XXY)? why?

Back 311

appear prominent

results from atrophy and crowding of tubules and elevation of gonadotropin concentrations

Front 312

what is Turner syndrome?

Back 312

X

female hypogonadism that is the result of complete or partial monosomy of the X chromosome

Front 313

what is the most common sex chromosome abnormality in females?

Back 313

Turner syndrome (X)

Front 314

what is the incidence of Turner syndrome (X)?

Back 314

1 in 2000 live-born females

Front 315

what disorder should immediately be brought to mind when a patient has a cystic hygroma?

Back 315

Turner's syndrome

Front 316

how do the most severely affected Turner syndrome patients present?

Back 316

Turner syndrome = X monosomy

most severely affected generally present during infancy with edema of the dorsum of the hand and foot due to lymph stasis, and sometimes swelling of the nape of the neck

Front 317

what is a cystic hygroma?

Back 317

a congenital multiloculated lymphatic lesion that can arise anywhere, but is classically found in the left posterior triangle of the neck

Front 318

what are the principal clinical features of Turner syndrome in the adolescent and adult patients?

Back 318

short stature
low posterior hairline
webbing of neck
broad chest
widely spaced nipples
aortic coarctation
cubitus valgus
streak ovaries
infertility
amenorrhea
pigmented nevi

Front 319

what is aortic coarctation?

Back 319

a narrowing of part of the aorta (the major artery leading out of the heart)

a birth defect

Front 320

what is the single most important cause of primary amenorrhea?

Back 320

Turner syndrome

Front 321

what immune problems are noted in Turner syndrome patients?

Back 321

approximately 50% of patients develop hypothyroidism as a result of autoantibodies that react with the thyroid gland

Front 322

what metabolic problems are noted in Turner syndrome patients?

Back 322

glucose intolerance
obesity
insulin resistance

(only present in a minority of patients)

Front 323

what happens to ovaries in Turner syndrome patients?

Back 323

develop normally early in embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes (complete by 2 years of age)

in a sense, "menopause occurs before menarche," and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries)

Front 324

define the term "true hermaphrodite"

Back 324

person with the presence of both ovarian and testicular tissue

Front 325

define the term "pseudohermaphrodite"

Back 325

person with a disagreement between the phenotypic and gonadal sex

Front 326

what is a female pseudohermaphrodite?

Back 326

person with ovaries but male external genitalia

Front 327

what is a male pseudohermaphrodite?

Back 327

person with testicular tissue but genitalia that ranges from ambiguous to completely female

Front 328

what is the basis of female pseudohermaphroditism?

Back 328

excessive and inappropriate exposure to androgenic steroids during the early part of gestation

Front 329

what is the cause of complete androgen insensitivity syndrome?

Back 329

aka testicular feminzation

results from mutations in the gene encoding the androgen receptor

Front 330

in fragile-X-syndrome, where do the causative trinucleotide expansions occur?

Back 330

oogonia

Front 331

in Huntington disease, where do the causative trinucleotide expansions occur?

Back 331

spermatids

Front 332

fragile-X-syndrome is a prototype of what kind of diseases?

Back 332

those in which the mutation is characterized by a long repeating sequence of three nucleotides

Front 333

what is the second most common genetic cause of mental retardation?

Back 333

fragile-X-syndrome

Front 334

what is the inheritance pattern of fragile-X-syndrome?

Back 334

X-linked transmission

Front 335

what are the mutations that cause fragile-X-syndrome?

Back 335

inducible cytogenetic abnormality in the X chromosome and an unusual mutation within the familial mental retardation-1 (FMR1) gene

Front 336

what are the clinical manifestations of fragile-X-syndrome in males?

Back 336

IQ between 20 and 60
long face with a large mandible
large everted ears
large testicles
hyperextensible joints
high arched palate
mitral valve prolapse

Front 337

what is macro-orchidism?

Back 337

large testicles

Front 338

what is the most distinctive feature of fragile-X-syndrome?

Back 338

macro-orchidism

present in more than 90% of post-pubertal males

Front 339

what are normal transmitting males in fragile-X-syndrome?

Back 339

males who are known to carry a fragile-X mutation, but are clinically and cytogenetically normal

(happens in about 20% of males)

Front 340

what is the incidence of fragile-X-syndrome in females?

Back 340

fragile-X-syndrome is an X-linked disorder, so it is more prominent in males

30-50% of carrier females are affected (i.e. mentally retarded)

Front 341

what is anticipation with respect to fragile-X-syndrome?

Back 341

clinical features of fragile-X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons

Front 342

how is anticipation explained?

Back 342

during the process of oogenesis, but not spermatogenesis, premutations (expansions of 55-200 CGG repeats) can be converted to mutations (expansions of 200-4000 CGG repeats) by triplet repeat amplification

Front 343

what is a feature that is unique to mitochondrial DNA? why?

Back 343

it is inherited from the mother only

ova contain numerous mitochondria within their abundant cytoplasm, whereas spermatazoa contain only a few, if any

Front 344

how many genes are contained in mitochondrial DNA?

Back 344

37

(22 are transcribed into tRNAs and 2 are transcribed into rRNAs)

Front 345

what DNA encodes enzymes involved in oxidative phosphorylation?

Back 345

mitochondrial DNA (mtDNA)

Front 346

what organs are mostly affected by mutations in mtDNA? why?

Back 346

CNS
skeletal muscle
cardiac muscle
liver
kidneys

these organs are most dependent on oxidative phosphorylation (mtDNA encodes the enzymes involved in oxidative phosphorylation)

Front 347

what is heteroplasmy?

Back 347

the presence of a mixture of more than one type of an organellar genome (mitochondrial DNA (mtDNA) or plastid DNA) within a cell or individual

Front 348

what is the threshold effect with respect to mitochondrial DNA?

Back 348

since most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mtDNA, it is possible and indeed very frequent for mutations to affect only some of the copies, while the remaining ones are unaffected

a minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease

the "threshold" is reached most easily in metabolically active tissues (CNS, skeletal muscle, cardiac muscle, liver, and kidneys)

Front 349

what is a prototype disorder of diseases associated with mitochondrial inheritance?

Back 349

Leber hereditary optic neuropathy

Front 350

what is the inheritance pattern of Leber hereditary optic neuropathy?

Back 350

mitochondrial inheritance

this is a neurodegenerative disease that is caused by mutations in mitochondrial DNA (responsible for ox-phos enzymes)

Front 351

what is Leber hereditary optic neuropathy?

Back 351

neurodegenerative disease that manifests as a progressive bilateral loss of central vision (impairment is first noted btwn ages 15 and 35)

caused by mutations in mitochondrial DNA (responsible for ox-phos enzymes)

Front 352

what is imprinting?

Back 352

selective inactivation of either a maternal or paternal allele

Front 353

what is maternal imprinting?

Back 353

transcriptional silencing of the maternal allele

Front 354

what is paternal imprinting?

Back 354

transcriptional silencing of the paternal allele

Front 355

where does imprinting occur?

Back 355

occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis

Front 356

how are imprinted genes found?

Back 356

can occur in isolation

more commonly they are found in groups that are regulated by common cis-acting elements called imprinting control regions

Front 357

what are the clinical characteristics of Prader-Willi syndrome?

Back 357

mental retardation
short stature
hypotonia
profound hyperphagia
obesity
small hands and feet
hypogonadism

Front 358

what are the clinical characteristics of Angelman syndrome?

Back 358

mental retardation
ataxic gait
seizures
inappropriate laughter

Front 359

what causes Prader-Willi syndrome?

Back 359

deletion of a portion of paternally derived chromosome 15

(same portion as in Angelman)

Front 360

what causes Angelman syndrome?

Back 360

deletion of a portion of maternally derived chromosome 15

(same portion as in Prader-Willi)

Front 361

patients afflicted with what illness are sometimes referred to as "happy puppets"? why?

Back 361

Angelman syndrome (deletion of a portion of maternal chromosome 15)

these patients characteristically present with ataxia and inappropriate laughter

Front 362

what is uniparental disomy?

Back 362

inheritance of both chromosomes of a pair from one parent

Front 363

what is the affected gene in Angelman syndrome?

Back 363

a ubiquitin ligase that is involved in catalyzing the transfer of activated ubiquitin to target protein substrates

Front 364

what gene is affected in Prader-Willi syndrome?

Back 364

no single gene has been implicated, but one that is included is a gene that encodes small nuclear riboprotein N (controls gene splicing; expressed highly in the brain and heart)

Front 365

what is the function of small nuclear riboprotein N?

Back 365

controls gene splicing

(expressed highly in the brain and heart)

Front 366

what are the two imprinting illnesses?

Back 366

Prader-Willi syndrome
Angelman syndrome

both are caused by a deletion of the same portion of chromosome 15 (Prader-Willi if the deletion affects the paternally derived chromosome 15; Angelman syndrome if the deletion affects the maternally derived chromosome 15)

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what are repeat-length polymorphisms?

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short repetitive sequences of DNA that are repeated a variable number of times in different people

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what are the two types of repeat-length polymorphisms?

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microsatellite repeats (<1 kilobase; repeat size of 2-6 base pairs)

minisatellite repeats (larger; 1-3 kilobase; repeat size of 15-70 base pairs)

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what stretches of DNA can be used to establish genetic identity for linkage analysis?

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microsatellites and minisatellites (repeat-length polymorphisms)

they are extremely variable within a given population

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what type of assays have been extensively validated and are now routinely used for determining paternity and for criminal investigations?

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panels of microsatellite marker PCR assays

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what is a southern blot?

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using a DNA probe to identify a specific sequence of genomic DNA

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what is FISH?

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fluorescence in Situ Hybridization

uses DNA probes that recognize sequences specific to particular chromosomal regions

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define epigenetics

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the study of heritable chemical modifications of DNA or chromatin that does not alter the DNA sequence itself

ex. methylation and acetylation of histones