Recessive Diseases Flashcards
(217 cards)
1
Q
What is mode of inheritance for DMD?
A
X-linked recessive
2
Q
What kinase is elevated in DMD?
A
serum creatine kianse
3
Q
What is most common cause of death for DMD?
A
cardiac or respiratory failure
4
Q
Which disease can you not lift your head when lying and which an you lift it?
A
cannot lift: DMD can lift: BMD
5
Q
Where is the mutation for DMD & BMD?
A
dystrophin
6
Q
What is type of mutation for DMD
A
null mutation, deletions, frameshifts, nonsense - complete loss of fuction
no dystrophin
7
Q
What is type of mutation for BMD?
A
in frame deletion
partially functional dystrophin
8
Q
Where are the deletions in dystrophon in BMD less severe?
A
in middle of dystrophin protein
9
Q
Do DMD pts reproduce?
A
No
10
Q
Do BMD pts reproduce?
A
yes
11
Q
If exon length is not a multiple fo three which MD is it?
A
DMD
12
Q
If exon length is a multiple of 3 what MD is it?
A
BMD
13
Q
What is a way to stop DMD from happening genetically?
A
have it Read through the stop codons
14
Q
Inborn error of metabolism means what?
A
disorder caused by deficiency of enzymes involved in metabolic pathways
15
Q
What is an enzymopathy?
A
general term for disease caused by enzyme deficiency
16
Q
What is mode of interitance for enzymopathies
A
almost always recessive
17
Q
Why are enzymopathies recessive?
A
the one allele produces enough phenotype needed
18
Q
How does pathology occur in enzymopahy?
A
disease occurs b/c of stubstrate accumulation and/or product deficiency
19
Q
Phenylketonuria, alkaptonuria, albanism, homocysteinuria, maple syrup urine disease are alle xamples of what kind of disease
A
amino acid metablism disease, they are enzymopathies
20
Q
what diseases occur due to mutation of Phe, Tyr metabolism pathway?
A
Phenylketonuria, alkaptonuria, albanism
21
Q
Can we synthesize phenylalanine?
A
No, get it from diet from proteins
22
Q
What aa does phenylalanine get turned into?
A
tyrosine
23
Q
can we synthesize tyrosine?
A
yes
24
Q
What important things is tyrosine used for?
A
tissue proteins, melanin, catecholamines, fumarate acetoacetate
25
Phenylalanine Hydroxylase (PAH) mutation is what disease?
Phenylketonuria (PKU)
26
enzyme: HGD is what disease?
alkaptonuria
27
What does PAH stand for?
Phenylalanine Hydroxylase
28
What does PKU stand for?
Phenylketonuria
29
PKU has elevated phenylalanine in the blood, what is the name of this?
hyperphenylalaninemia
30
What is main clinical presentation of PKU?
mental retardation
31
Mental retardation, musty odor, developmental delays, micrcephaly, hypopigmentation are symptoms of what disease?
PKU
32
Accumulating phenylalanine is converted to what in PKU
Phenylpyruvate and other ketoacids
33
What is the affect of the accumulation of phenylalanine that is converted to Phenylpyruvate and other ketoacids?
toxic effects
34
What is the treatment of PKU
dietary restriction of Phe (phenylalanine)
35
When does pt need to start PKU treatment?
within first month
36
When does pt need to start PKU treatment?
within first month
37
what disease helped initiate use of newborn screening
PKU
38
If pts with PKU has restricted diet in first month what is there IQ?
normal
39
If a pt has been on restricted diet and has normal IQ, what happens if they go on normal diet
It very slowly lowers their IQ, takes years to lower it
40
If a female with PKU becomes pregnant, what is it very important she do?
stick to restricted low Phe diet
41
What happens if embryo is exposed to high Phe even if they are heterozygous
the baby is affected b/c of the high exposure to Phe
42
What gene is affected in PKU?
PAH
43
Describe allelic heterogeneity in PKU
b/w different races there are different mutations on same gene that can cause PKU
44
What is hyperphenylalaninemia?
elevated phenylalanine in blood
45
Any mutation lead that leads to defeiciency of cofactor will also lead to what
hyperphenylalniniemia
46
what are the two ways you can end up with tetrahydrobiopterin?
two enzymes will block BH4 and lead to hyperphenylalninemaia
tyrosine hydroxylase
tryptophan hydroxylase
47
besides accumulation of phenylalanine, what happens in BH4 deficiency?
defieicency of neurotransmitters and serotonin
48
What are two ways to treat BH4 defieciency?
restricted diet
| give them neurotransmitter precursers
49
What are the 5 genes that can lead to hyperphenylalaninemia?
PKU
2 genes in BH4 synthesis
2 genes involved in BH4 recyling
50
What is the name of the black urine disease?
alkaptonuria
51
where is the enzyme deficiency in alkaptonuria?
homogentisate 1,2-dioxygenase (HGD)
52
What does HGD stand for?
homogentisate 1,2-dioxygenase
53
What is HGD often referred to as?
homogentisic acid oxidase (HGO)
54
what is mode of inheritance for alkaptonuria?
AR
55
What accumulates in alkaptonuria?
Homogentisic Acid
56
What happens with accumulation of Homogentisic Acid?
it oxidizes, and the products accumulate in soft tissues
57
What is ochronosis
bluish-black discoloration of soft tissues
58
the damage to cartilage in alkaptonuria can cause what?
osteoarthritis
59
What can potentiall yhappen to heart in alkaptonuria?
calcification of aortic valve
60
What is mode of inheritance for oculocutaneous abinism?
AR
61
OCA1 is what?
oculocutaneous albinism
62
where is deficiency in OCA1?
tyroinase (TYR)
63
why does OCA1 cause lack of pigment in skin?
inabilityt o convert tyrosine to melanin
64
what are the two varients of OCA1?
OCA1A & OCA1B
65
which varient of OCA1 is most severe?
OCA1A
66
What is OCA1B?
oculocutaneous albinism, less severe, residual activity
67
What is OCA1A?
oculocutaneous albinism, the severe form, no pigmentation, easily burned, visual acuity defects
68
Where is defieiceny in homocystinuria?
cystathionine beta synthase
69
what does CBS stand for?
cystathionine Beta synthase
70
what is mode of inhertiance for homocystinuria?
AR
71
What cofactor does CBS need?
Pyridoxal phosphate
72
what does PLP stand for?
pyridoxal phosphate
73
What is clinical presentation of homocystinuria
```
intellectual disability
seizures
nearsightedness, lens dislocation
osteoporosis
musculoskeletal defomritions ( long bones, similar looking to marfan syndrome)
```
74
PLP is an active form of what?
VitB6 (a vitamin)
75
What is a way to treat about 1/2 cases of Homocystinuria
give very high dosage of vitamin B6
76
What is VitB6 and its characteristics?
water soluble, not toxic vitamin
77
Why does treatment of high dosage of Vitamin B6 only work for half the cases?
mutation decreases cofactor binding or another mutation that could affect substrate binding, etc.
78
What enzyme is defective in maple syrup urine disease?
Branched-chain α-keto acid dehydrogenase complex
79
What does BCKDC stand for?
Branched-chain α-keto acid dehydrogenase complex
80
In maple syrup urine disease there are defective metabolism of branched-chain aa:
Val, Leu, Ile
81
What leads to pathology of maple syrup urine disease
accumulation of branched chain aa
82
What is clinical presentation of maple syrup urine disease?
mental retardation
seizures
urine - sweet smell (like maple syrup)
fatal if untreated
83
How do you treat maple syrup urine disease?
dietary restriction of branched-chain aa via artifical diet
84
Are Val, Leu, Ile essential aa?
yes
85
What are hemoglobinopathies?
defect in hemoglobin
86
what is basic structure of hemoglobin?
tetramer- has 4 subunits
87
What is hemoglobin function in RBC?
oxygen carrier in RBC
88
each subunit have what in hemoglobin?
heme & iron that oxygen binds to
89
every hemoglobin tetramer can carry how many oxygen molecuels?
4
90
What are the two broad categories of hemoglobinopathies?
structural varients
| thalassemias
91
describe the hemoglobin structural varients
defectiv polypeptide, protein still there but does not function correctly. usually due to beta globin mutation
92
what is most important beta globin hemoglobin mutation?
sickle cell disease
93
where is mutation in thalassemias?
in alpha or beta globin
94
what leads to pathology of disease in thalassemias?
imbalance of relative amounts of alpha and beta chains
95
What is MOI in hemoglobinopathies
AR
96
What is MOI in hemoglobinopathies
AR
97
where does the majority of hemoglobinopathy incidence occur?
tropical parts of world (like sickle cell)
98
HbS stands for what
sickle cell
99
--/aa (alpha) is most common in what population?
SE asian & china
100
Beta0 is most common in what population?
italian/greek
101
alpha and beta globin belong to what?
families
102
alpha globin cluster on what chromosome
16
103
bet algobin cluster on chromosome what?
11
104
how did globin gene families arise?
gene duplications
105
on alpha globin locus there's duplications, most of them are what?
non-functional
106
how many genes are there for alpha globin?
two
107
describe the relationship of the two alpha globin genes
they are expressed at the same level, very similar
108
does alpha or beta globin family have more functional genes
beta
109
during development different genes are expressed @ different times, describe how gene expression occurs on alpha globin locust?
it starts on zeta globin and then moves right
110
what is the first alpha globin expressed?
zeta globin
111
when is zeta globin used?
just in early embryogenesis
112
what is first beta globin expressed
epsilon
113
what is second beta globin expressed
gamma
114
what are main forms of beta globin expressed in adults?
beta globin (and very small amounts of delta globin)
115
When does gamma beta globin end?
6 months after birth
116
delta globin is expressed when?
very low levels throughout life, starts being expressed just after birth
117
Hemoglobin A is what?
adult form of hemoglobin
118
Hemoglobin A2 is what
variant adult hemoglobin
| Alpha and delta
119
fetal hemoglobin is what?
hemoglobin F: alpha and gamma globin
120
gower 1 is what hemoglobin?
embryonic
121
If BH4 synthesis or recycling is defective what are the two results?
Hyperphenylalaninemia
| Deficiency of catecholamines and serotonin
122
Why will mental retardation still occur if a pt with BH4 defieicency is put on a Phe restricted diet?
there is still deficiency of neurotransmitters
123
What are the three important aa in BH4 defeciency?
Tyrosine, Tryptophan, Phenylalanine
| Tyr, Trp, Phe
124
What is important product of tyr hydroxylase pathway?
NE & E
| noepinepherine & epinepherine
125
What is important product of trp hyrxoylase pathway?
serotonin
126
What does Hb stand for?
hemoglobin
127
What is the composition of HbA?
two alpha and two beta hemoglobin
128
What is the composition of HbA2?
two alpha and two delta
129
What is the composition of HbF?
two alpha & two gamma
130
What is the composition of Hb Gower 1?
two zita and two epsilon
131
At what age would you find HbF?
fetus
132
At what age would you find Hb Gower 1?
embryo
133
HbF has higher affinity for oxygen than what, and why is it important?
HbA - allows transport of oxygen from mom to baby
134
Expression of hemoglobin is controlled by what?
LCR
135
What is LCR
an enhancer
136
What does LCR stand for?
locus control region
137
In embryonic DNA LCR would drive expression of what?
epsilon
138
In fetal DNA LCR would drive expression of what?
gamma
139
In adult DNA LCR will drive expression of what?
Beta and some delta
140
Hemoglobinopathies: structural variants, describe
normal amount of protein is produced but the protein that is produced is abnormal
141
HbC is what mutation
beta: same codon as HbS, codon 6 glu to lys
| E6K
142
How will normal hemoglobin vs. sickle cell migrate differently on gel?
sickle cell migrates more slowly, not as negatively charged
143
How does HbC run on gel compared to HbS and normal Hb?
HbC runs slower than both of them
144
What is milder than sickle cell, no sickling of RBCs, asymptomatic, mild hemolytic anemia, splenomegaly
HbC
145
What is a thalassemia caused by?
imbalance in production of globin chains
146
The imbalance in production of globin chains causes what?
accumulation of free globin chains → insoluble, preciptate
147
What is Heinz body?
inclusion of denatured hemoglobin
148
What is hemolysis?
the rupture or destruction of red blood cells.
149
What is being produced less in alpha thalassemia?
alpha globin is decreased or absent
150
What kind of mutation normally occurs in alpha thalassemia?
gene deltions
151
Chromosme 16 has how many copies of alpha globin gene
2 identical copies
152
How many forms of alpha thalassemia are there?
4
153
What are the four forms of alpha thalassemia?
silent carrier
alpha thalassemia trait
hemoglobin H disease
hydrops fetalis
154
What is the clinical presentation of silent carrier of alpha thalassemia
none
155
what is the clinical presentation of alpha thalassemia trait
none or minimal anemia under stress
156
what is the clinical presentation of hemoglobin H disease
microcytic, hypochromic anemia
157
What is the clinical presentation of hydrops fetalis?
lethal in utero
158
HbH and Hb Barts have what important characteristics?
insoluble
159
If three genes are deleted what form of alpha thalassemia is it?
hemoglobin H disease
160
If two genes are deleted what form of alpha thalssemai is it?
alpha thalassemia trait
161
a-/a- means what
a alpha gene is deleted on each chromosome
162
a-/a- are called what?
alpha heterozygote
163
a+-thal means what
alpha thalassemia trait
164
What form of alpha thalassemia could a parent have a child with hydrops fetalis?
only when an entire chromosome doesn't have any correct alpha hemoglobin, as parent donates their entire chromosome
165
What kind of hemoglobin is produced in hydrops fetalis?
Hb Barts
166
severe anemia, edema, heart failure, fatal in utero in 3rd trimester is what sdiseae?
hydrops fetalis
167
--/-- is what alpha thalassemia disease/
hydrops fetalis
168
Does a pt with hydrops fetalis have alpha hemoglobin?
no
169
a-/-- is what alpha thalassemia disease?
HbH disease
170
How much alpha globin is produed in HbH disease?
25%
171
What is kind of hemoglobin is produced in HbH disease?
HbH (4 beta)
172
microcytic, hypochromic anemia, hepatomegaly, splenomegaly is what disease?
HbH disease
173
What does HbCS stand for?
Hb Constant Spring
174
where is mutation in HbCS?
in alpha globin, a nonstop mutation
175
what is a nonstop mutation
stop codon changed to aa codon
176
describe what happens to cause HbCS
stop codon ismutated to aa codon resulting in longer protein
177
Describe the RNA in HbCS
unstable
178
HbCS is phenotypically similar to what
HbH
179
Which forms of hemoglobin have very high affinities for oxygen but do not release the oxygen into the tissues?
Hb Barts, HbH, HbCS
180
Since the two HBA genes are identical, what cn happen in meiosis
homologous recombination
| unequal crossing over
181
what is the result of unequal crossing over of HBA genes
one chromosome will lose a copy of gene and the other will gain a copy
182
What is the result of having 3 copies of HBS on one chromosome
no change in phenotype
183
What is the result of having 3 copies of HBS on one chromosome
no change in phenotype
184
What is wrong in beta thalassemia
synthesis of beta globin is decreased or absent
185
what does HBB stand for
beta globin
186
when does phenotype usually present in beta thalassemia and why
in 1st year, after birth, beta globin doesnt take over until after birth
187
What is the name of the heterozygous carrier state for beta thalassemia
beta thalassemia minor
188
what is the phenotype of beta thalassemia minor
asymptomatic
189
how much beta globin is present in beta thalassemia major
none
190
what is the normal mutation for beta thalassemia major
null mutation
191
what disease has severe microcytic hypochromic anemia, hepatosplenomegly, ,bone marrow expansion, skeletal changes, require regular blood transfusions (iron overload secondary to transfussions)
β-Thalassemia Major
192
What is the main form of beta thalassemia major
β° Thalassemia
193
What is beta thalassemia intermedia
like β° Thalassemia but less severe
194
What is the normal mutation for mutations in beta thalassemia vs alpha
null mutations with no functional protein produced
| Not complete deletions (like alpha)
195
what is the most common cause of beta thalassemia
point mutations
196
what do missense mutations usually result in
specific structural disorders with different specific phenotypes, not thalassemias
197
How is Hb Lepore caused by what?
unequal crossing over b/w beta globin and delta globin
198
How do beta and delta gobin have crossing over
they are so similar they can misalign
199
What is the result of crossing over of beta and delta globin
it will be a hybrid gene, so part delta part beta
200
what is the issue in Hb lepore
not enough beta globin being produced because delta globin is expressed at very low levels
201
why is beta globin expressed at low levels in Hb lepore
because of the crossing over its a gene hybrid and the recombined gene uses promoter from delta globin
202
why is beta globin expressed at low levels in Hb lepore
because of the crossing over its a gene hybrid and the recombined gene uses promoter from delta globin
203
Is the recombined beta delta gene in Hb lepore functional?
yes but expressed at low levels so presents as beta thalassemia
204
Is the recombined beta delta gene in Hb lepore functional?
yes but expressed at low levels so presents as beta thalassemia
205
What does HPFH stand for
Hereditary Persistence of Fetal Hemoglobin
206
What is phenotype of HPFH
normal
207
What causes HPFH?
deletions of beta globin & delta globin
208
In HPFH what does LCR activate?
gamma globin promoters
209
What does AIP stand for?
acute intermittent porphyria
210
What is the major acute hepatic porphyria?
AIP
211
What is deficient in AIP?
porphobilinogen deaminase
212
What is MOI for AIP?
AD
213
Clinical presentation: Latent prior to puberty
Abdominal pain, weakness
Neuropsychiatric disturbances, hallucinations
Wine red urine
No photosensitivity
Exacerbated by hormones, drugs & diet
is what disease?
AIP
214
What is the less common acute hepatic porphyria?
VP
215
What does VP stand for?
variegate porphyria
216
What is deficient in VP?
Protoporphyrinogen oxidase
217
clinical presentation: Abdominal pain, weakness
Neuropsychiatric disturbances, hallucinations
Photosensitivity
Exacerbated by hormones, drugs & diet
is what disease?
VP
