Robbins Ch. 5 Flashcards
1
Q
Human genetic disorders can be broadly classified into what three categories?
A
1: Disorders related to mutations in single genes with large effects
2: Chromosomal disorders
3: Complex multigenic disorders
2
Q
Disorders related to mutations in single genes with large effects are often also called what?
A
Mendelian disorders
3
Q
A permanent change in the DNA is called what?
A
a mutation
4
Q
A point mutation that alters the amino acid sequence of the coded protein is often termed what?
A
missense mutation
5
Q
If a point mutation causes a change in the amino acid sequence of the coded protein but the amino acid is similar and function doesn’t change much, what is it called?
A
a conservative missense mutation
6
Q
What type of mutation is the sickle mutation affecting the beta-globin chain of hemoglobin?
A
nonconservative missense mutation
7
Q
Specifically describe the sickle mutation affecting the beta-globin chain of hemoglobin?
A
CTC –> CAC; mRNA GAG–> GUG; AA Glutamic acid –>valine
8
Q
If a point mutation changes the amino acid codon to a stop codon what is it called?
A
nonsense mutation
9
Q
name the disease: Point mutation of beta-globin affecting glutamine (CAG) to a stop codon (UAG)
A
Beta-Thalassemia; severe form of anemia
10
Q
Is the mutation for cystic fibrosis (CF) a frameshift mutation?
A
No (deletion of a multiple of 3)
11
Q
What amino acid is lacking in the CF mutation?
A
F(508); Phe
12
Q
describe change in allele involving glycosyltransferase from ABO A allele to ABO O allele
A
single base deletion leading to a frameshift mutation
13
Q
Describe the mutation in Tay-Sachs disease
A
4 base insertion in the hexosaminidase A leading to a frameshift mutation
14
Q
Fragile X syndrome is what type of mutation?
A
trinucleotide-repeat mutation
15
Q
What nucleotides are shared in almost all affected trinucleotide repeat mutations?
A
G and C
16
Q
What’s the repeat for Fragile X syndrome?
A
250 to 4000 tandem repeats of CGG within a gene called familial mental retardation 1 (FMR1)
17
Q
What is the distinguishing feature of trinucleotide repeat mutations?
A
They are dynamic; the degree of amplification increases during gametogenesis
18
Q
What does congenital mean?
A
Born with; Some genetic diseases are not congenetal (huntington’s)
19
Q
Explain the difference between sickle cell trait and sickle cell anemia?
A
individuals with sickle cell trait are heterozygotes so they only have a proportion of HbS so red blood cell sickling only happens under lowered oxygen tension
20
Q
What is it called when both alleles contribute to the phenotype?
A
codominance; (histobompatibility and blood group antigens)
21
Q
What is it called when a single mutant gene leads to many end effects?
A
pleiotropism; (sickle cell)
22
Q
What is it called when mutations at several genetic loci produce the same trait?
A
genetic heterogeneity
23
Q
What is it called when individuals inherit the mutant gene but are phenotypically normal?
A
incomplete penetrance
24
Q
What is it called if a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals?
A
variable expressivity
25
When an autosomal dominant mutation impairs the function of a normal allele what is this called?
dominant negative
26
A male is said to be what for X-linked mutant genes?
hemizygous
27
Vitamin D-resistant rickets is an example of what type of inheritance?
X-linked dominant
28
What structural protein is defective in osteogenesis imperfecta?
collagen
29
What structural protein is defective in hereditary spherocytosis?
spectrin
30
What structural protein is defective in muscular dystrophies?
dystrophin
31
Are thalassemias associated defective structure or amount of globin chains?
Amount
32
What drug induces hemolytic anemia in individuals with a deficiency in G6PD enzyme?
antimalarial drug primaquine
33
What are the principal manifestations of Marfan syndrome?
changes in the skeleton, eyes, and cardiovascular system
34
The familial cases of marfan syndrome show what type of inheritance?
autosomal dominant
35
What protein is defective in marfan syndrome?
extracellular glycoprotein called fibrillin-1
36
What are the 2 ways by which loss of fibrillin leads to the clinical manifestations of Marfan Syndrome?
1: loss of structural support in microfibril rich connective tissue
2: excessive activation of TGF-beta signaling
37
Fibrillin is a component of microfibrils that provide scaffolding for what?
tropoelastin
38
Where are microfibrils particularly abundant?
Aorta, Ligaments, and the ciliary zonules that support the lens
39
Marfan syndrome is a mutation of what gene?
FBN1
40
What chromosome is FBN1 mapped on?
15
41
Mutations of the FBN2 gene give rise to what?
congenital contractural arachnodactyly
42
What chromosome is FBN2 mapped on?
5
43
For these people with clinical features of marfan syndrome but no mutation in FBN1 (MFS2), what is the etiology of the disease?
gain of function mutation in genes that encode TGF-beta receptors
44
Clinical dignosis of marfan syndrome is currently based on what?
revised Ghent criteria
45
What is the mainstay of medical treatment for Marfan Syndrome?
administration of Beta-blockers
46
Ehlers-Danlos Syndromes (EDS) are a defect in what structural protein?
Collagen
47
What type of joints do people with EDS have?
hyperextensible and hypermobile. contortionists
48
what type of skin do people with EDS have?
extraordinarily stretchable, extremely fragile, and vulnerable to trauma
49
What often ruptures in vascular EDS?
Colon and Large arteries
50
What often ruptures in kyphoscoliosis EDS?
Ocular fragility with rupture of cornea and retinal detachment
51
What is herniates in Classic EDS?
diaphragmatic hernia
52
What is the most common recessive form of EDS?
kyphoscoliosis
53
The gene defective in kyphoscoliosis EDS encodes what enzyme?
Lysyl hydroxylase
54
Vascular EDS results in an abnormality of what type of collagen?
Type III
55
What gene has a mutation in vascular EDS?
COL3A1
56
What type of inheritance is vascular EDS?
autosomal dominant because structural, not enzymatic
57
Which types of EDS is the fundamental defect in the conversion of type 1 procollagen to collagen?
arthrochalasia and dermatosparaxis
58
one of 2 genes are mutated in Arthrochalasia? What are the genes?
COL1A1 and COL1A2
59
Describe the mechanism for arthrochalasia EDS
structurally abnormal Pro-alpha 1 or 2 chains that resist cleavage of N terminal peptides. Patients with single mutant allele have 50% abnormal but heterozygotes manifest the disease because its structural (autosomal dominant)
60
Describe the mechanism for dermatosparaxis EDS
mutations in the procollagen-N-peptidase genes for cleavage. Enzyme deficiency so it's autosomal recessive
61
In 30-50% of classic EDS cases, mutations in what genes are found?
Type V collagen. (COL5A1 and COL5A2)
62
Often times in Classical EDS there is no collagen disfunction, but it is believed that other ECM molecules are abnormal. One example is an EDS-like condition caused by mutation in a large multimeric protein that affects the synthesis and fibril formation of type VI and type I collagen. What is the mutation in?
Tenascin-X
63
familial hypercholesterolemia is a mutation in the gene coding for what?
receptor for LDL
64
Heterozygotes with one mutant gene for the LDL receptor, representing about 1 in 500 individuals have from birth a 2 to 3 fold elevation of plasma cholesterol level, leading to what?
tendinous xanthomas and premature atherosclerosis in adult life
65
What's the increase in plasma cholesterol levels in individuals homozygous for the LDL receptor mutation?
5 to 6 fold increase
66
What may develop in homozygotes for the LDL receptor gene mutation?
skin xanthomas
| coronary, cerebral, and peripheral vascular atherosclerosis
67
Myocardial infarction may occur before what age in homozygotes for the LDL receptor gene mutation?
age 20
68
What is the first step in synthesis and catabolism of choelsterol?
secretion of VLDL by the liver into the blood stream
69
Describe the contents of VLDLs
rich in triglycerides but lesser amounts of cholesteryl esters
70
When a VLDL reaches the capillaries of adipose or muscle, it is cleaved by what?
lipoprotein lipase
71
Cleavage by lipoprotein lipase of the VLDL extracts what?
most of the triglycerides
72
What is the resulting molecule after lipoprotein lipase cleaves VLDL?
IDL (intermediate-density lipase)
73
What 3 apoproteins are on VLDL?
ApoC
ApoE
B-100
74
What 2 apoproteins are left on IDL?
B-100
| ApoE
75
What receptor recognized the B-100 and ApoE on the IDL to be taken up by the liver?
LDL receptor
76
What happens to the IDL that is not taken up by the liver?
further metobolic processing that removes most of the remaining triglycerides and ApoE yielding cholesterol-rich LDL particles
77
What Apoprotein is left on LDL?
B-100
78
What is the immediate and major source of plasma LDL?
IDL
79
LDL binds to receptors, which are clustered in specialized regions of the plasma membrane called what?
coated pits
80
The exit of cholesterol from the lysosomes requires the action of what 2 proteins?
NPC1 and NPC2
81
What 2 things does intracellular cholesterol suppress?
1: cholesterol synthesis by inhibiting HMG CoA reductase
2: synthesis of LDL receptors thus protecting the cells from excessive accumulation
82
What does intracellular cholesterol activate?
acyl-coenzyme A: favoring esterification and storage of excess cholesterol
83
With familial hypercholesterolemia there is an increase in what kind of uptake of LDL?
Scavenger receptor-mediated traffic into cell of the mononuclear phagocyte system and possibly the vascular walls
84
What Type of LDL receptor mutation is this: relatively uncommon and leads to a complete failure of synthesis of the receptor protein (null allele).
Type I
85
What Type of LDL receptor mutation is this: Fairly common; they encode receptor proteins that accumulate in the endoplasmic reticulum because their folding defects make it impossible for them to be transported to the Golgi complex
Type II
86
What Type of LDL receptor mutation is this: affect the LDL-binding domain of the receptor; the encoded proteins reach the cell surface but fail to bind LDL or do so poorly.
Type III
87
What Type of LDL receptor mutation is this: encode proteins that are synthesized and transported to the cell surface efficiently. They bind LDL normally, but they fail to localize in coated pits and hence the bound LDL in not internalized.
Type IV
88
What Type of LDL receptor mutation is this: encode proteins that are expressed on the cell surface, can bind LDL, and can be interalized; however the pH-dependent dissociation of the receptor and the bound LDL fails to occur. such receptors are trapped in the endosome, where they are degraded, and hence they fail to recycle to the cell surface.
Type V
89
How do statins work?
suppress intracellular cholesterol synthesis by inhibiting HMG CoA reductase, allowing for greater synthesis of LDL receptors
90
What are lysosomal enzymes (acid hydrolases) tagged with in the Golgi?
mannose-6-phosphate
91
When a lysosomal enzyme deficiency leads to the accumulation of the partially degraded insoluble metabolite within the lysosome, what is that called?
primary accumulation
92
Lysosomal disfunction leading to disrupted autophagy is called what?
secondary accumulation
93
What is it called when an exogenous competitive inhibitor of an ezyme can, paradoxically, bind to the mutatn enzyme and act as the "folding template" that assists proper folding of the enzyme and thus prevent its degradation.
molecular chaperone therapy
94
Defective hydrolysis of gangliosides occurs in what diseases and what location?
GM1 and GM2 gangliosidoses. Brain
95
What organs are frequently enlarged in several forms of lysosomal storage disorders?
Spleen and Liver
96
What is the most common form of GM2 gangliosidosis?
Tay-sachs disease
97
What mutation causes Tay-sachs disease?
mutations in the alpha-subunit locus on chromosome 15 that cause a severe deficiency of hexosamindase A
98
Tay-Sachs Disease is prevalent among who?
jews of Eastern European origin (Ashkenazic)
99
When do signs and symptoms of Tay-Sachs begin to manifest?
6 months
100
What are the clinical signs of Tay-Sachs?
Motor incoordination
Mental obtundation leading to muscular flaccidity
Blindness
increased dementia
101
When does death occur in Tay-Sachs?
2-3
102
What disease is caused by a mutation in the beta-subunit of hexosaminidase locus rather than the alpha subunit found in Tay-Sachs?
Sandhoff disease
103
Name the disease: characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase?
Neimann-Pick Disease Types A and B
104
Which Neimann-Pick Disease is a severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting?
Type A
105
When does death occur in Type A Niemann-Pick Disease?
within the first 3 years of life
106
Which niemann-pick Disease to patients have organomegaly but generally no central nervous system involvement and survive into adulthood?
Type B
107
What ethnic group commonly have Niemann-Pick Disease Types A and B?
Ashkenazi jews
108
Where does the gene for acid sphingomyelinase map to?
chromosome 11
109
What genes are responsible for Niemann-Pick Disease Type C (NPC)?
NPC1 and NPC 2
110
NPC is due to a primary defect in what?
non enzymatic lipid transport
111
Which NPC gene product is membrane bound and which is soluble?
NPC1 is membrane bound and NPC2 is lipid soluble
112
What neurological deficits are found with NPC?
- ataxia
- vertical supranuclear gaze
- palsy
- dystonia
- Dysarthria
- psychomotor regression
113
Name the Disease: a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase
Gaucher Disease
114
What is the most common lysosomal storage disorder?
Gaucher disease
115
The affected gene in Gaucher Disease encodes glucocerebrosidase. What does this enzyme normally do?
cleaves the glucose residue from ceramide
116
Besides the storage burden of Glucocerebrosides in Gaucher Disease, what else contributes to the pathology?
secretion of cytokines IL-1, IL-6, and TNF from activated macrophages
117
Which type of Gaucher Disease:Storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain. Splenic and skeletal involvments dominate this pattern. reduced but detectable levels of glucocerebrosidase activity and longevity is shortened but not markedly.
Type I or nonneuronopathic
118
Which type of Gaucher Disease: Infantile acute cerebral pattern. No preference for Jews. NO detectable glucocerebrosidase activity in the tissue. Hepatosplenomegaly is seen but the clinical picture is dominated by progressive central nervous system involvment leading to death at an early age.
Type II or acute neuronopathic
119
Which type of Gaucher Disease: Intermediate type. systemic involvment but progressive central nervous system disease that usually begins in adolescence or early adulthood.
Type III
120
What hemopathology is commonly found with Gaucher disease?
Pancytopenia or thrombocytopenia secondary to hypersplenism
121
What is the mainstay treatment of Gaucher Disease?
Replacement therapy with recombinant enzymes
122
Because the fundamental defect of Gaucher Disease resides in mononuclear phagocytic cells originating from marrow stem cells, what can be curative?
allogeneic hematopoietic stem cell transplantation
123
Name the syndrome: genetically determined deficiency of enzymes in the degradation of mucopolysaccharides (glycosaminoglycans)
mucopolysaccharidoses (MPS)
124
What glycosaminoglycans accumulate in MPSs?
- dermatan sulfate
- heparan sulfate
- keratan sulfate
- chondroitin sulfate
125
What inheritance pattern do all except one MPSs show?
autosomal recessive
126
The exceptional MPS is what inheritance and called what?
X-linked recessive. Hunter syndrome
127
In general, MPSs are progressive disorders characterized b what?
- coarse facial features
- clouding of the cornea
- joint stiffness
- mental retardation
- urinary excretion of the accumulated mucopolysaccharides is often increased
128
Name the disease: deficiency of alpha-1-iduronidase. one of the most severe forms of MPS. Affected children appear normal at birth but develop hepatosplenomegaly by age 6 to 24 months. Growth is retarded, and, as in other forms of MPS, they develop coarse facial features and skeletal deformities.
Hurler syndrome, also called MPS I-H
129
When does death occur in Hurler syndrome and why?
Ages 6-10. cardiovascular complications.
130
Name the Disease: X-linked. Absence of corneal clouding and milder clinical course than other MPSs
Hunter syndrome or MPS II
131
Name the lysosomal storage diseases
- Tay-Sachs Disease
- Niemann-Pick Diseases types A and B
- Niemann-Pick Disease Type C
- Gaucher Disease
- Mucopolysaccharidoses
132
During degradation of Glycogen, distinct phosphorylases in the liver and muscle split glucose-1-phosphate from the glycogen until about 4 glucose residues remain on each branch, leaving a branched oligosaccharide called what?
Limit dextrin
133
What in a lysosome can also degrade Glycogen?
acid maltase
134
Name the enzyme: Glucose --> G6P
hexokinase (glucokinase)
135
Name the enzyme: G6P --> G1P
phosphoglucomutase
136
What does G1P get converted to?
uridine diphosphoglucose
137
What are the 3 major subgroups of glycogenoses?
- hepatic forms
- myopathic forms
- Glycogen storage diseases associated with either deficiency of alpha-glucosidase (acid maltase) or lack of branching enzymes
138
Name the disease: Deficiency of the enzyme glucose-6-phosphatase. hepatic hypoglycemic form of glycogen storage disease.
Von Gierke Disease or type 1 glycogenosis
139
Deficiencies in liver phosphorylase and debranching enzyme, both involved in the breakdown of glycogen, are what subgroup of glycogenoses?
hepatic form
140
What features dominate the clinical picture in hepatic form glycogenoses?
hepatic enlargement and hypoglycemia
141
Name the Disease: deficiency in muscle phosphorylase
McArdle disease or Type V glycogenosis
142
Name the Disease: deficiency in muscle phosphofructokinase
Type VII glycogen storage disease
143
What do people with myopathic for of glycogenoses present with?
muscle cramps after exercise and lactate levels in the blood fail to rise after exercise due to a block in glycolysis
144
Name the Disease: deficiency in acid maltase. lysosomal storage of glycogen
Type II glycogenosis or Pompe Disease
145
What is the most prominent feature of type II glycogenosis or Pompe Disease?
Cardiomegaly
146
What subgroup of Glycogen storage diseases are associated with death early in life?
Glycogen storage diseases associated with either deficiency of alpha-glucosidase (acid maltase) or lack of branching enzymes
147
When karyotyping to study chromosomes, cells are arrested when?
metaphase
148
What is used to arrest cells in metaphase?
mitotic spindle inhibitors (Colcemid)
149
What is the most common Staining technique for karyotyping?
Giemsa stain - G banding
150
The short arm of the chromosome are designated what letter?
p
151
The long arm of the chromosome are designated what letter?
q
152
What is any exact multiple of the haploid number of chromosomes (23) called?
euploid
153
A number of chromosomes not an exact multiple of 23 is called what?
aneuploidy
154
What are the usual causes of aneuploidy?
nondisjunction and anaphase lag
155
fertilization of a normal gamete and a gamete that has went through nondisjunction gives what result?
trisomy (2n+1) or monosomy (2n-1)
156
Does monosomy generally permit life?
no
157
what is it called when mitotic errors in early development give rise to two or more populations of cells with different chromosome complement, in the same individual?
mosaicism
158
Name the syndrome: 45X/47XXX mosaic
Turner Syndrome
159
What is produced when a break occurs at both ends of the chromosome with fusion of the damaged ends?
ring chromosome
160
an inversion involving only one arm of the chromosome is known as what?
paracentric
161
an inversion caused by breaks on opposite sides of the centromere is called what?
pericentric
162
What is it called when one arm of a chromosome is lost and the remaining are is duplicated?
isochromosome
163
what is the most common isochromosome present in live births?
the long arm of the X. i(X)(q10)
164
What is it called when there are single breaks in each of 2 chromosomes with exchange of material?
balanced reciprical translocation
165
Translocation between two acrocentric chromosomes is called what?
robertsonian translocation or centric fusion
166
What is the most common of the chromosomal disorders and is a major cause of mental retardation?
Trisomy 21 (down syndrome)
167
What has a strong influence on the incidence of trisomy 21?
maternal age
168
in 95% of the cases of trisomy 21, the extra chromosome comes from which parent?
mother
169
In about 4% of cases of Down syndrome, where is the extra chromosomal material derived from?
The presence of a robertsonian translocation of the long arm of chromosome 21 to another acrocentric chromosome (eg. 22 or 14)
170
Approximately 1% of Down syndrome patients are What?
mosaics, having a mixture of cells with 46 or 47 chromosomes
171
What are the diagnostic clinical features of Down syndrome?
Flat facial profile, oblique palpebral fissures, and epicanthic folds
172
approximately 40% of Down Syndrome patients have what?
congenital heart disease
173
What other congenital malformations are common with down syndrome?
atresias of the esophagus and small bowel
174
What is responsible for a majority of the deaths in infancy or early childhood of down syndrome patients?
Cardiac problems
175
Children with trisomy 21 have a 10 to 20 fold increased risk of developing what?
acute leukemia
176
Virtually all patients with trisomy 21 older than age 40 develop what?
neuropathologic changes characteristic of Alzheimer Disease
177
How is trisomy 21 diagnosed prenatally and noninvasively?
Maternal blood
178
Trisomy 18 is called what?
Edwards syndrome
179
Trisomy 13 is called what?
Patau syndrome
180
What are the clinical features of Chromosome 22q11.2 Deletion Syndrome?
- congenital heart defects
- abnormalities of the palate
- facial dysmorphism
- developmental delay
- variable degrees of T-cell immunodeficiency
- hypocalcemia
181
The clinical features of Chromosome 22q11.2 Deletion syndrome were previously considered to represent what 2 different disorders?
DiGeorge Syndrome and velocardiofacial syndrome
182
what psychotic illnesses to patients with Chromosome 22q11.2 deletion syndrome have a higher risk for?
schizophrenia and bipolar disorders
183
What test is used to determine Chromosome 22q11.2 Deletion syndrome over Digeorge and velocardiofacial syndrome?
FISH
184
What gene is most closely associated with the phenotypic features of chromosome 22q11.2 deletion syndrome?
TBX1
185
Where is the TBX1 gene expressed?
- pharyngeal mesenchyme
| - endodermal pouch from which facial stuctures, thymus and parathyroid are derived
186
What is the target of TBX1?
PAX9, a gene that controls the development of the palate, parathyroids, and thymus
187
Why are imbalances of Sex chromosomes more tolerated than similar imbalances of autosomal chromosomes?
- lyonization or inactivation of all but one X chromosome
| - the modest amount of genetic information carried by the Y chromosome
188
The X chromosome that is not active undergoes what?
heteropyknosis and is rendered inactive
189
Inactivation of either the maternal or paternal X occurs at random among all the cells of the blastocyst on what day of embryonic life?
5.5
190
The molecular basis of X inactivation involves what gene?
XIST
191
What is the product of the XIST gene?
long noncoding RNA that is retained in the nucleus whre is coats the X chromosome that it is derived from and initiates a gene-silencing process by chromatin modification and DNA methylation
192
Which arm on the inactivated X chromosome has a bigger proportion of genes that escape inactivation?
p arm
193
How do we know that both X chromosomes are needed?
patients with monosomy of the X chromosome (Turner Syndrome: 45X) have severe somatic and gonadal abnormalites.
194
Both X chromosomes are require for what?
normal oogenesis
195
What gene dictates testicular development?
SRY
196
All Y chromosome deletions are associated with what?
azoospermia
197
Name the Syndrome: Male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes.
Klinefelter syndrome
198
What are common features of Klinefelter syndrome?
- elongated body
- abnormally long legs
- small atrophic testes
- lack of secondary male characteristics
- gynecomastia may be present
- mitral valve prolapse in about 50%
199
What is the only consistent finding of klinefelter syndrome?
hypogonadism
200
In klinefelter syndrome, FSH levels in plasma are what?
Testosterone?
estradiol?
elevated
variably reduced
Elevated by unknown mechanism
201
Patients with Klinefelter syndrom have a higher risk for what?
- Breast cancer
- extragonadal germ cell tumors
- autoimmune diseases such as systemic lupus erythematosus
202
What is the classic karyotype of Klinefelter syndrome?
47,XXY
203
What is the trinucleotide repeat found on androgen receptors encoded by the X chromosome?
CAG
204
Long CAG repeats are more or less sensitive?
less
205
In klinefelter syndrome, the X chromosome with long or short CAG sequences is silenced?
short; exacerbating the hypogonadism
206
Name the Syndrome: complete or partial monosomy of the X chromosome and characterized primarily by hypogonadism in phenotypic females
Turner Syndrome
207
What are the 3 different karyotypic abnormalities found in Turner syndrome?
- Approximately 57% are missing an entire X chromosome (45,X)
- Structural abnormality producing partial monosomy of X chromosome
- Mosaics
208
Turner Syndrome Mosaics with the karyotype 45,X/46,XY have a higher risk for developing what?
gonadal tumor (gonadoblastoma)
209
The most severely affected patients of Turner Syndrome generally present during infancy with what?
- edema of the dorsum of the hand and foot
- swelling of the nape of the neck (cystic hygroma)
- Swellings subside and leave bilateral neck webbings
- Congenital heart disease also common
210
What is the most important cause of increased mortality in children with Turner Syndrome?
Cardiovascular Abnormalities
211
what is of particular importance in establishing the diagnosis of Turner Syndrome?
Shortness of stature and amenorrhea
212
What is the single most important cause of primary amenorrhea?
Turner Syndrome
213
Growth hormone therapy is often used in treatment of turner syndrome. What is sometimes found in these patients that will be worsened by giving them growth hormones?
insulin resistance
214
In Turner Syndrome, ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles known as what?
Streak ovaries
215
What gene involved in Turner Syndrome is responsible for the short stature and also has a homologue on the Y chromosome?
SHOX
216
Where on the chromosome is the SHOX gene located?
Xp22.33
217
Genetic sex is determined by what?
presence or absence of a Y chromosome
218
Gonadal sex is based on what?
histologic characteristics of the gonads
219
Ductal sex depends on what?
presence of derivatives of the mullerian or wolffian ducts
220
Phenotypic or genital sex is based on what?
appearance of the external genitalia
221
A true hermaphrodite implies what?
the presence of both ovarian and testicular tissue
222
A pseudo-hermaphrodite represents what?
a disagreement between the phenotypic and gonadal sex
223
Trinucleotide repeats are an important cause of what type of genetic disease?
neurodegenerative disorders
224
In Fragile X Syndrome, trinucleotide expansion occur during what?
oogenesis
225
in Huntington disease, trinucleotide expansion occurs during what?
speratogenesis
226
What are the 3 mechanisms by which unstable repeats cause disease?
- loss of function
- Toxic gain of function
- Toxic gain of function mediated by mRNA
227
When unstable repeats cause loss of function, what part of the gene are they usually in?
non coding part
228
when unstable repeats cause a toxic gain of function, what part of the gene are they usually in?
coding region
229
Huntington Disease uses what mechanism of repeat?
toxic gain of function
230
Repeats that affect the coding region are usually what repeats?
CAG; polyglutamine diseases
231
What is the morphologic hallmark of polyglutamine (gain of function repeat) diseases?
accumulation of aggregated mutant proteins in large intranuclear inclusions
232
What is the second most common genetic cause of mental retardation?
Fragile X syndrome
233
What is the characteristic physical phenotype of males with fragile X syndrome?
- long face with large mandible
- Large everted ears
- Large testicles (macro-orchidism)
234
What is the most distinctive feature of fragile X syndrome, which is observed in at least 90% of affected postpubertal males?
macro-orchidism (Large testicles)
235
Carrier males of the fragile X mutation are clinically normal and transmit the gene to phenotypically normal daughters to affected grandchildren. They are also called what?
normal transmitting males
236
What percent of carrier males of the fragile X muations are actually affected (mentally retarded)?
30-50
237
Clinical feature 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. This is called what?
Anticipation
238
The fragile X mutation is localized where?
Xq27.3
239
Normal transmitting males and carrier females of the fragile X mutation have how many CGG repeats?
55-200
240
55-200 CGG repeats is called what?
premutations
241
Affected individuals of fragile X syndrome have how many CGG repeats?
200-4000 (full mutations)
242
What process causes premutations for Fragile X to be converted to mutations by triplet-repeat amplification?
oogenesis; NOT spermatogenesis
243
When trinucleotide repeats in the FMR1 gene exceed approximately 230, what happens?
The DNA of the entire 5' region of the gene becomes abnormally methylated and this extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1 = absence of FMRP
244
What are the 2 functions of FMRP (familial mental retardation protein)?
- selectively bind mRNAs associated with polysomes and regulate their intracellular transport to dentrites
- translation regulator
245
What type of mRNAs are subject to shuttling by FMRP?
mRNAs encoding proteins that regulate synaptic function
246
FMRP suppresses protein synthesis from the bound mRNAs in response to signaling through what receptors?
group I metabotropic glutamate receptors (mGlu-R)
247
What is now the method of choice for diagnoses of Fragile X syndrome?
PCR-based detection
248
A feature unique to mtDNA is what?
maternal inheritance
249
mutations affecting mitochondrial genes exert their deleterious effects primarily on what organs?
- CNS
- skeletal muscle
- cardiac muscle
- liver
- kidneys
250
When individuals harbor both wild-type and mutant mtDNA, it is known as what?
heteroplasmy
251
What disease is the prototype for mitochondrial inheritance?
Leber hereditary optic neuropathy
252
transcriptional silencing of the maternal allele is known as what?
maternal imprinting (and visa versa for paternal)
253
How does genetic imprinting regulate?
- DNA methylation at CG nucleotides
| - Histone H4 deacetylation and methylation
254
Name the Disease: Mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism
Prader-Willi syndrome
255
All cases of Prader-Willi Syndrome, the deletion affects what?
paternally derived chromosome 15
256
Cases of Angelman syndrome are born with a deletion of what?
The same region as Prader-Willi but on maternal chromosome 15
257
Name the disease: mentally retarded, ataxic gait, seizure, and inapproptiate laughter
Angelman Syndrome (happy puppets)
258
What band is deleted in Prader-Willi and Angelman syndrome?
q12 in the long arm of chromosome 15
259
What are the 3 mechanisms that give rise to Prader-Willi and Angelman?
- Deletions
- uniparent disomy
- defective imprinting
260
In Angelman syndrome, what is the affected gene and gene product?
UBE3A; ubiquitin ligase
261
Describe the imprinting of UBE3A gene in angelman syndrome.
imprinted on the paternal chromosome and expressed from the maternal allele primarily in specific regions of the brain. The imprinting is tissue-specific so it is expressed from both alleles in most tissues
262
What family of genes are involved in Prader-Willi syndrome and what do they encode?
SNORP family; small nucleolar RNAs which modify ribosomal RNAs
263
Explain how an autosomal dominant disorder can have phenotypically normal parents that have more than one affected child (osteogenesis imperfecta)?
Gonadal mosaicism; a mutation that occurs postzygotically affects only cells destined to form gonads in the parent so all somatic cells are normal.
264
What's the diagnoses? HER2 (ERBB2) amplification
Breast cancer
265
Diagnose: EGFR (ERBB1) mutation
Lung cancer
266
Diagnose: BCR-ABL fusion genes
chronic myelogenous leukemia (CML)
