Genetic Diseases Flashcards
1
Q
Duchenne Muscular Dystrophy - Inheritance
A
X-linked Recessive
Affects 1/3000 males
2
Q
Duchenne Muscular Dystrophy - Clinical Presentation
A
Onset before 5 yrs, wheelchair by 13, median age of death is 30 years.
Progressive myopathy; large calves, gowers maneuver, cardiac compromise, abnormal gait, 10X creatine Kinase levels
3
Q
Duchenne Muscular Dystrophy - Mechanism
A
DMD (dysrophin) mutation on Ch Xp12.2
Absence of Dystrophin
Loss of function due to large deletions of exons, nonsense frameshift mutations
High new mutation rate due to largest gene in genome.
4
Q
DMD associated dilated cardiomyopathy
A
early death
dilated cardiomyopathy presenting between 20-40
no skeletal involvement
milder symptoms
5
Q
Hereditary Neuropathy with Liability to Pressure Paulsy - Inheritance
A
Autosomal Dominant
6
Q
Hereditary Neuropathy with Liability to Pressure Paulsy - Clinical Presentation
A
Temporary neuropathy when pressure is applied; limgs can go to sleep for longer periods of time.
First attack in 2nd grade
Recovery is incomplete and leads to disability
7
Q
Hereditary Neuropathy with Liability to Pressure Paulsy - Disease mechanism
A
Loss of function of PMP22 ch 17 due to unequal crossing over
PMP22 is integral glycoprotein in nerves
8
Q
Osteogenesis Imperfecta Type I - inheritance
A
Autosomal Dominant
1/30,000 to 50,000
9
Q
Osteogenesis Imperfecta Type I - Clinical Presentation
A
Variable expressivity
Multiple fractures, short stature, adult onset hearing loss, blue sclerae
10
Q
Osteogenesis Imperfecta Type I - Mutation
A
Loss of Function
Non-sense frameshift mutation of COL1A1 ch17 causes pre-mature termination
mRNA to be degraded, so less collagen can be made
11
Q
Charcot Marie Tooth Type 1A - inheritance
A
Autosomal Dominant
fully penetrant
variable expressivity
12
Q
Charcot Marie Tooth Type 1A - Clinical Presentation
A
Demyelination of motor and sensory neurons lower extremity weakness muscle atrophy foot deformity - hammertoes progressive
13
Q
Charcot Marie Tooth Type 1A - Mechanism
A
Gain of function - demyelination
duplication of PMP22 gene 17p11.2
14
Q
Osteogenesis Imperfecta Type II, III and IV - Inheritance
A
Autosomal Dominant
15
Q
Osteogenesis Imperfecta Type II, III and IV - Clinical Presentation
A
More severe form
Brittle bones, increased fractures, blue sclerae
16
Q
Osteogenesis Imperfecta Type II, III and IV - Mechanism
A
Novel Property Mutation
COL1A2 ch 7 protein is mutated with different folding forming collagen trimers that are mutated.
17
Q
Huntington Disease - Inheritance
A
Autosomal Dominant 1/10,000 Anticipation Early onset - parental Later onset - maternal
18
Q
Huntington Disease - Clinical Presentation
A
Progressive neurodegenerative disorder with adult onset motor, cognitive, and psychiatric disturbances
death 15 years after onset
19
Q
Huntington Disease - Mechanism
A
Tri nucleotide CAG repeats in HTT ch 4 huntingtin gene exon
number of repeats corresponds to age of onset.
20
Q
Myotonic Dystrophy 1 - inheritance
A
Autosomal Dominant
21
Q
Myotonic Dystrophy 1 - Clinical Presentation
A
Droopy eye, intellectual difficutly, hypotonia
22
Q
Myotonic Dystrophy 1 - Mechanism
A
Increased CTG repeats in 3’ UTR of DMPK ch 15 gene
Correspond to age of onset and progression
23
Q
Phenylketouria - inheritance
A
Autosomal Recessive
1/10,000
carrier frequency of 1/50 in Northern European
24
Q
Phenylketouria - Clinical Presentation
A
Epilepsy, mental retardation, hyperactivity, tremor, gait disorders
High Phe is toxic to CNS
25
PKU Mechanism
Paritial or complete loss of function
Over 400 alleles identified and most compound heterozygotes.
1) defect in pAH gene encoding phenylalanin hydorxylase that catalyzes Phe --> Tyr
2) 1-3% mutation in BH4 synthesis or regeneration
26
BH4 mutation
PKU mutation
| causes decreased levels of serotonin and dopamine as well
27
PKU treatment
Low-Phe diet should be maintained all life.
| BH4 deficient should be treated with oral BH4 and supplemented with NTs.
28
Maternal PKU
maintain low Phe-diet during childbearing years and pregnancy.
Not on low Phe diet, give birth to malformed children and mental retardation even without genotype.
Due to Phe passing BBB and preventing necessary materials from accessing brain.
29
Newborn Screening of PKU
Mass Spec to sort by size and charge.
Compare normal [Phe] to [tyr]
Must be done enough after birth but before CNS is affected.
30
Alpha1-Antitrypsin Deficiency - Inheritance
Autosomal Recessive
More common in N. Europeans
1/2500 affected
1/25 carriers
31
Alpha1-Antitrypsin Deficiency - Clinical
Emphysema, liver cirrhosis/cancer due to accumulation of misfolded alpha1-AT proteins
32
Alpha1-Antitrypsin Deficiency - Mechanism
Defective alpha-1-AT protein
smoking accelerates disease
Z allele (Glu342Lys) expresses misfolded protein that aggregates in ER of liver to cuase liver damage.
S allel (Glu264Val) expresses an unstable protein that is less effective.
33
Alpha1-Antitrypsin Deficiency - Treatment
Treatment of COPD by bronchodilators, vaccinations against flu and pnemonia, pulmonary rehab, lung transplant
Developing treatments: enzyme repalcement therapy, gene thearpy, release misfolded AAT into blood.
34
Alpha1-Antitrypsin
ATT (SERPINA1)
made in liver
serine protease inhibitor that binds to elastase and inhibits it.
35
Elastase
inhibited by ATT
destroys connected tissue in lung (elastin) to cause emphysema
Made by neutrophils and allows mobilization of lung cells to promote healing.
36
LTB4
secreted from macrophages in lung to make attract neutrophils to make more elastase.
37
Tay-Sachs Disease - Inheritance
Autosomal Recessive
1/360,000
1/3,6000 A Jews
38
Tay-Sachs Disease - Clinical Presentation
Progressive degeneration of CNS, onset at 3-6 months
muscle weakness, loss of voluntary movement, seizures
Eye abnormality/visual loss - cherry red spot
39
Tay-Sachs Disease - Mechanism
Lysosomal storage disease
Defect in alpha subunit (HEXA on Ch1 5) of Hexoamidinidase A that degrades GM2 ganglioside.
Most common mutation is a 4bp insertion in exon 11 of HEXA
40
Sandhoff Disease - Inheritance
Autosomal Recessive
41
Sandhoff Disease - Clinical Presentation
Similar to Tay-Sachs, but more severe
| Defects in HEXB CH 5 makingbeta subunit in HexA and HexB inative
42
Sandoff vs. Tay-Sachs
TS only has mutation in HexA
| S: mutation in HexA and HexB due to defective Beta subunit
43
AB variant of Tay-Sachs
rare form where both HexA and HexB are normal, but GM2 accumulates due to defect in GM2 activator protein that facilitates interaction between GM2 and HexA enzyme.
44
Cystic Fibrosis - Clinical Presentation
Salty skin, poor growth and weight gain despite normal food intake
accumulation of thick, sticky mucus, frequent chest infections, coughing
45
Cystic Fibrosis - Mechanism
mutation in CFTR gene (ch 7) needed to regulate sweat, digestive juice and mucus by regulating Na/K channels across epithelial
46
Hereditary Hemachromatosis - inheritance
Autosomal Recessive
47
Hereditary Hemachromatosis - Clinical Presentation
Hepatic cirrhosis in combo with hypopituitarism, cardiomyopathy, diabetes, arthritis, hyperpigmentation
iron overload
48
Hereditary Hemachromatosis - mechansim
mutation in HFE gene on Ch 6
| important in iron regulation
49
Achondroplasia - Inheritance
Autosomal Dominant
1/15,000-40,000
80% new mutation (1138)
100% penetrance
50
Achondroplasia - Clinical Pres
```
Small stature (4'3" and 4')
Rhizomelic limb shortening, short fingers, genu varum, trident hands, large head, frontal bossing, small foramen magnum
```
51
Achondroplasia - Mechanism
Gain of Function
Gly380Arg in FGFR3 (CH 4) Gene
Regulates bone growth by limited formation of bone from cartilage.
52
Retinoblastoma - Inheritance
Autosomal Dominance
1/15000
incomplete penetrance
53
Retinoblastoma - Clinical Presentation
malignant tumor of retina
Absence of red retina
strabismus, visual deterioration
54
Retinoblastoma- Mechanism
Mutation in RB1 gene Ch13
RB is a tumor supressor
Loss of function - destabilize or cant associated with enzymes for deacytylation
55
Neurofibromatosis Type I - Inheritance
```
Autosomal Dominant
1/3000
50% new mutation rate
Variable expressivity
extreme pleiotropy
```
56
Neurofibromatosis Type I - Clinical Presentation
Cafe au lait, axillary and inguinal freckling, multiple neurofibromas, lisch nodules (spots.bumps on eyes)
57
Neurofibromatosis Type I - Mechanism
Mutation on NF1 Ch17
NF1 regulates cell proliferation and is a tumor suppressor
Loss of function
Must have mutation on both genes to show phenotype
58
Tuberous Sclerosis - inheritance
```
Autosomal Dominant
1/6000
Variable expressivity
1/3 inherited; 2/3 de novo
fully penetrant
```
59
Tuberous Sclerosis - clinical Presentation
Hypopigmented patches, angiofibroma, shangreen patch, renal cysts, lymphangiolelomyomatosis, cardiac rhabdomyoma, CNS issues, seizures, ADHD cognitive disorders
60
Tuberous Sclerosis - mechanism
Mutation in TSC1 or TSC2
encode hemartin and tuberin porteins that regulate cell growth and proliferation
on Ch9 and 16
Loss of function mutations
61
Marfan Syndrome - inheritance
AD
1.5000 births
25% new mutation
variable expressivity
62
Marfan Syndrome - Clinical Presentation
connective tissue disorder in aorta, ocular, skeletal, and cardio
aoritc root enlargement, ectopia lentis, scoliosis, pectus excavatum
63
Marfan - mechanism
FBN1 fibrillin - an extracellular matrix proin on Ch15
Negative activity mutation
Severe reduction in #
64
AD Polycystic Kidney Disease - Inheritance
AD
| 1/1000
65
AD Polycystic Kidney Disease - Clinical
Enlarged kidney with multiple cysts, end stage renal disease, renal cysts in other organs, intracranial aneurysms
66
AD Polycystic Kidney Disease - mechanism
ADPKD-1 mutation on Ch16 on Ch4
| Locus heterogeneity
67
Familial Hypercholesterolemia - inheritance
AD
| 1/500
68
Familial Hypercholesterolemia - Clinical Presentation
High cholesterol
deposits of cholesterol throughout body
premature coronary artery disease
69
Familial Hypercholesterolemia - mechaism
Mutation in gene encoding LDL receptor (cant clear LDL from blood stream)
70
Fragile X-Syndrome - Inheritance
X-linked Dominant
1:2500-4000 in males
1/7000-8000 in males
Anticipatory and maternal bias
71
Fragile X-Syndrome - Clinical Presentation
Mental deficiency, large ears and long face, macroorchism (enlarged testicles), autism like, hand flapping/biting
72
Fragile X-Syndrome - Mechansim
Trinucleotide repeats over 200 in FMR1 in 5' UTR due to hypermethylation and silencing.
73
Fragile X-associated Tremor/Ataxia Syndrome - mechanism
from fragile X premutation (59-200 CGG repeats) that aren't hypermethylated but make more RNA
74
Fragile X-associated Tremor/Ataxia Syndrome - Clinical Presentation
Parkinson like features, gait ataxis, premature ovarian failure in women
75
haplotype effect in Fragile X
AGG repeats within CGG to reduce risk
76
what disease has repeats in 5' UTR
Fragile X and FTAXS
77
What disease has repeats in introns
Friedrich Ataxis and myotonic dystrophy
78
what disease has repeats in exons
Huntington
79
What disease has repeats in 3' UTR
Myotonic Dystrophy 1
80
Hemophilia A - Inheritance
x linked recessive
1:4000 males
10% female carriers
81
Hemophilia A - Clinical Presentation
Bleeding complications due to decreased clotting
82
Hemophilia A - Mechanism
Factor VIII deficiency du to mutation in Chx
| can be upplemented by Factor VIII
83
Turner Syndrome - Inheritance
45, X
Sex chromosome numerical disorder
Affects 1/2000-1/5000 new born girls
84
Turner Syndrome - Cardio
Bicuspid aoritc valve, coarctation, systemic hypertension, prolonged QTc, persistend left SVC
85
Turner Syndrome - Eye
Inner canthal folds, Ptosis, Blue sclera
86
Turner Syndrome - skeletal system
cubitus valgus, short 4th metacarpal, short stature, shield chest
87
Turner Syndrome - Neck
webbed neck, cystic hygroma in utero, low hairline
88
Turner Syndrome - Learning abnormalities
difficulty in math, visual spatial skills, low non-verbal skills
89
Turner Syndrome - Endocrine
Hypothyroidism, gonadal dysgenesis
90
Turner Syndrome - Physical features
webbed neck, shield chest, unilateral breasts, widely spaced nipples, rudimentary ovaries, brown nevi, low hairline, elbow deformity, edema in hands and feet at birth
91
Challenges associated with Turner Across lifetime
1) Infertility
2) stature
3) sexual development
4) concerns regarding health and aging
92
Pitfalls of Turner syndrome
1) secret keeping
2) difficulty conveying infertility
3) negative experiences with physician
93
Klinefelter Syndrome - inheritance
1:500-1:1000
Sex chromosome non-disjunction
47 XXY
94
Klinefelter Syndrome - Clinical Presentation
gonadal dysgenesis/hypogondasim: small testes and decreased body hair, infertility
quiet, wide waist, not broad shoulders.
hypospandias (urethra placement)
95
Klinefelter Syndrome - mechansim
Meitoic Non-disjunction
equal distribution between father and mother NDJ
25% are moscaic with increasing X becomes more severe
96
Rett Syndrome - Inheritance
X-Dominant
1:10,000 females
95% due to new mutations
97
Rett Syndrome - Clinical Presentation
Loss of movement and coordiantion; acquired microcephaly, seizures, abnormal hand mvmt
98
Rett Syndrome - Mechanism
mutation in MECP2 (methyl CPg Binding Protein) that is a loss of nerve function
99
Hypophosphatemic Rickets - inheritance
X-dominant
| 1:20,000
100
Hypophosphatemic Rickets - Clinical Presentation
Hypoposphatemia (low phosphate levels)
| short, bone deformity
101
Hypophosphatemic Rickets - Mechanism
Mutation in PHEX gene that regulates fibroblast growth factor
Cant reabsorb phosphate into blood stream
102
Jacob Syndrome - Inheritance
Sex Chromosome
47 XYY
1/900
103
Jacob Syndrome - Clinical Presentation
usually indistinguishable from normal physically and mentally
Increased risk of behavior or education problems, delayed speech and language, autism spectrum
tall
104
Congenital Adrenal Hyperplasia _ inheritance and clinical presentation
Autosomal Recessive 46, XX
1/25,000
Ambiguous genitalia, masculization of females
105
Congenital Adrenal Hyperplasia - Mechanism
21-Hydroxylase deficiency so that ACTH is increased and the adrenals are hyperplastic, overproducing androgens
106
Dosage Sensitive Sex Reversal - Inheritance and Clinical Presentation
X-linked Recessive
| development of ovaries even in presence of SRY
107
Dosage Sensitive Sex Reversal - Mechanism
Duplication of DAX1 gene, a nuclear hormone receptor promoting female sex development
108
5 alpha reductase deficiency - inheritance and clinical
46, XY
Incomplete phallic dvpt, severe pseudovaginal perineal, ambiguous genitalia that begins normal male development during puberty.
109
5 alpha reductase deficiency - Mechanism
Alpha reductase mutation - normally required to convert testosterone to dihydrotestosterone.
110
Androgen Insensitivity Syndrome - Inheritance and clinical Presentation
X-linked
| mild to severe under virilization
111
Androgen Insensitivity Syndrome - mechanism
mutation in androgen receptor so body doesn't recognize it or respond to testosterone
112
Disorders of SRY Gene - Inheritance and Clinical
Y linked - deletion or absence to result in sex reversal to phenotypically normal female (decreased production of anti-mullerian hormone)
Ectopic presence: phenotypically normal males
(increased anti-mullerian hormone)
113
Denys Drash and Frasier Syndrome
46 XY sex reversal
chronic kidney dsiease
wilm's tumor risk
Mechanism: mutation in WT1 (a TF in SRY gene)
114
Non-Syndromic Deafness - Inheritance
```
Autosomal Dominant (progressive childhood deafness)
Autosomal Recessive (congenital deafness)
1/2 of children have congenital and 3/4 or those are non-syndromic (occur in isolation)
```
115
Non-Syndromic Deafness - Mechanism
Allelic Heterogeneity
GJB2 most commonly mutated in DFBN1 protein
interferes with gap junctions, but does not affect vestibular system or auditory nerve.
loss of function
116
Non-Syndromic Deafness - treatment
Newborn screening for detection
| hearing aids, cochlear implants, speech and sign language therapy
117
Syndromic Deafness
Deafness associated syndromes
| General intellecutal-disability, seizures, dysmorphic syndromes
118
Usher Syndrome
AR
| Deafness with pigmentosa
119
Pendred Syndrome
AR
| deafness with thryoid goiter
120
Jervell and Lange Nielson Syndrome
AR
| Arrhythmia or sudden death with deafness
121
Waardenburg Syndrome
AD
| White forelock with deafness
122
Neurofibromatosis Type II
8th Nerve Schwannomas with deafness
123
Fabry Disease - Inheritance and clincial
X linked
Neurologic pains, reduced sweating, risk of stroke, progressive renal failure, risk of heart attach, hypertrophy of cardiac tissue
124
Fabry Disease - Mechanism
Deficiency of alpha-galactosidase protein misfolding causes accumulation of glycosphingolipids and microvascualr damage
125
Fabry Disease - treatment
Chaperone based therapy that helps alpha-galactosidase A fold correctly
ERT
126
Down Syndrome - inheritance
Chromosomal abnormality Trisomy 21
| 1/900
127
Down Syndrome - Clinical Presentation
mid-face hypoplasia, short stature, hypotonia, intellectual disability
Congenital malformations: endocardial cushions, esophageal and duodenal atresia, GI anomalies, hirshprung disease
conjunctivitis, myopia, chronic ear infections, diabetes, decreased fertility, luekemia, AD, autism
128
Down Syndrome- mechanism
95% materal NDJ
3-4% robersonian translocation
1-2% mosaic
129
Trisomy 13 - inheritance and clinical
Patau's
Trisomy 13
growth retardation, intellecutual disability, sloping forehad, misfomed ears, cleft lip/palate, heart defects, urogenital defects
130
Trisomy 18
Edward's syndrome
| small for gestation age, microcphaly, clenched hands, overlapping fingers, rocker bottom feet, heart/brain abnomralities
131
Prader-Willi Syndrome - inheritance/mutation
Due to imprinting erros on paternal ch15.
1) deletion
2) uniparental disomy of maternal
3) imprinting errors
132
Prader-Willi Syndrome - testing
Methylation of Ch15
| FISh
133
Prader-Willi Syndrome - phenotype
hypotonic, almond shaped eye, lighter pigmentation, undescended testicles, severe feeding problem as infant, but overeating as toddler, leading to obesity and sleep apnea
134
Prader-Willi Syndrome - developmental delays
1) motor delay
2) excessive complusion disorder
3) violence from withholding food
135
IMaternally inherited interstitial duplication
to make partial trisomy
Duplication of Ch15
Hypotonic, autism
Paternally are phenotypically normal
136
Angelman Syndrome - inheritance and clinical
Maternal deletion of 15ch
due to deletion, two copies of pateral allel, imprinting defect, UBE-3A mutation
Seizures, severe intellectual disability, short,
137
WAGR Syndrome - Clinical and mechanism
wilms tumor, aniridia, genitourinary anomilies, Intellecutal disability
Interstitial deletion of Ch11p13
can be seen by chromosome analysis or FISH
138
Digeorge Syndrome - clinical and mechanism
absent of hypoplastic thymus and parathyroid gland, congenital heart disease
Del 22q11.2
139
Acute Lymphomatic Leukemia - inheritance
ALL
| Hyperdiploidy
140
Acute Lymphomatic Leukemia - Clinical
downs much more likely to develop 20-100x
| enlarged spleen, joint or hip pain, anmeia, thrombocytopenia
141
Chronic Myelogenous Leukemia - inheritance/mechanism
CML
| Bcr-Abl translocation (9:22) in bone marrow
142
Chronic Myelogenous Leukemia - clinical
enlarged spleen, joint or hip pain, anmeia, thrombocytopenia
143
Chronic Myelogenous Leukemia - treatment/detection
FISH fusion
| Gleevec treatment
144
Acute Promyeloid Leukemia - inheritance/mechaism
APL/PML
PML-RARA translocation 15:17
viewing Auer rods (cytosolic precip) is diagnostic
145
Acute Promyeloid Leukemia - treatment/detection
FIsh Fusion
| treatment with Retinoic acid - vitamin A
146
IDIC15
```
inverted duplicated isochromosome 15
hypotonic with autism
Inverted and euplicated isochorome 15
have extra ch
maternally inherited
```
147
Gaucher Disease inheritance
Autosomal Recessive
1/50,000
1/450 in AJew
148
Gaucher Disease - clinical
hepatosplenomegaly, thrombocytopenia, anemia, joint pain, nose bleeds, CNS issue
149
Gaucher Disease - mechanism
Build up of glucocerebrosides in macrophage lysosomes due to lack of glucocerebrosidase function - called gaucher cells that get stuck in liver and spleen
150
Pompe Disease - inheritance and clinical
AR
| progressive muscle failure, cardiomegaly, hypotonia, respiratory distress, feeding difficulties, failure to thrive
151
Pompe Disease - Mechanism
accumulation of glycogen in lysosome due to deficient lysosomal acid alpha-glucosidase enzyme
152
Progeria - inheritance and clinical
De novo dominant
| premature aging syndrome
153
Progeria Mechanism
point mutation in Lamin A/C gene yielding abnormal progerin protein that targets to Nuclear membrane
154
Progeria treamtnet
Farnesyl transferase inhibitors reduce progerin sequesteration in nuclear membrane
155
Kearns-Sayre Syndrome - inheritance and clinical
mito
1/100,000
Pigmentary retinopathy, difficulty moving eye, atexia, cardic conductance defects, deafness, kidney issues
156
Kearns-Sayre Syndrome mechanism
large deletion in mtDNA that removes 12 genes
157
Mitochondria Encephalomyopathy Lactic Acidosis and Stroke like episodes (MELAS) inheritance and clinical
Mito I
| strokes, muscle weakness, seizures, elevated lactic acidosis in chidlren
158
MERRF
Myloclonic epilepsy with Ragged red Fibers
seizures, ataxis, dementia
mutaiton in MT-TK gene
159
Leber Hereditary optic neuropathy
Mito inheritance
| bilateral subacute vision failure
160
Hb Kempsy
Higher binding affinity for O2,but can't release in tissues.
| Leads to increased erythropoietin production and polycythemia
161
Hb Kansas
low affinity for O2 to lead to anemia and cyanosis
162
Sickle Cell
HbS
AR
Common in AA (10%)
base mutation in codon 6 form Glutamate to Valine to make less soluble when bound to O2.
163
Sickle Cell treatment
Byrate to increase fetal Hb and reduce polymerization of bS
164
Sickle Cell testing
BetaS has altered restriction site for MstII, so ou get one 1.35 kb fragment instead of two fragments as with BetaA
165
Hemoglobin C
```
HbC
AR
Milder form of hemolytic anmemia
Due to mutation in codon 6 of beta globin from glutamate to lysine.
less solube than HbA to form crystals
```
166
HbS or HbC traits
heterozygotes with HbA
| clinically normal except severe pO2 stress
167
HbSC
compound heterzygote
| milder anemia than sickle cell
168
HbEE
common in Southeast asia
mutation in HbBeta chain
mild hemolytic anemia and mild splenomegaly
Lysine instead of glutamate in codon 26
169
Alpha-Thalassemias
deletions in one or both alpha globin genes
make gamma or beta in excess
affects both fetal and adult Hb
170
Hydrops Fetalis
--/--
double deletion leads to 0% globin
fetal death because Bart's Hb is no sufficient to bring to life.
common in Southweat asia
171
Alpha-Thallasemia trait -1
```
aa/--
mild anemia
newborn: F,A, Barts
50% globin
prevantl in Southeast asia
resutls in --/--, a-/--, and aa/--
low or normal-low MCV
```
172
Alpha-Thallasemia trait -2
```
a-/a-
mild anemia
50% globin
prevalent in africa, med, asia
creates a-/a-
low or normal low MCV
```
173
HbH disease
a-/--
Severe anmeia
25% globin levels
beta4 Hb
174
Silent carrier for alpha thalassemia
aa/a-
50% globin
normal MVC
175
Beta Thalassemia
low to zero beta globin production, alpha globin made in excess
post natal effect only
due to mutation in promoter, splicing, coding, LCR, and beta-gene cluster
176
Cooley's Anemia
```
B-Thal Major
AR
Severe anemia
(--/--) or (--/Bmutation)
RBC are destroyed after released, thinking bone cortex, enlarged liver and spleen
low MCV
require blood transfusion and chealtor
Newborn screening: fetal only
```
177
Beta Thalassemia Minor
No clinical presentation (very mild)
normal to low MCV
WT/-- or WT/Mut
178
Beta Thal Int
```
AR
2 mildly abnormal genes
mild to moderate anemia
low MCV
sometimes tranfusion dependent
```
179
Beta+ Thalassemia
AR
Most common form 90%
mutation that affects trascription, RNA processing, and stability
some beta made, so HbA is present
180
Beta0 Thalassemia
AR
zero beta globin synthesis, so no HbA is present
5% Hb level due to a2/g2 or a2/d2
deletion of beta lgobin gene, early truncation, no mRNA synthesis
181
Dela-Beta0 thalassemia
AR
No delta and beta due to deletion of coding sequence for both globins.
Milder clinical phenotype than 0 because remaining gamma genes are still active after birth instead of switching off.
HbF compensates for absence of HbA to make about 5-18% normal Hb levels.
182
Gamma Thalassemia
deletion of gamma
| only significant at birth, overcome by 6 months of life
183
Delta Thalassmia
deletion of delta globin
| not a problem by itself, but when combined with beta more phenotypically present.
184
HPFH
hereditary persistence of Fetal hemoglobin
AR
Gamma globin still synthesized due to mutation that doesn't switch from beta to gamma.
100% Hb (at level of 17-35%)
185
HPFH methcanism
No beta or gamma synthesis due to deletions in both genes to cause increased expression:
1) Extended deletion of additional downstream sequences, brings a cis-acting enhancer closer to gamma-globin gene
2) Mutations in promoter region of one of two gamma-globin genes that destroy binding site of nearby repressor, relieving postnatal repression of gamma.
