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Genetic Diseases Flashcards

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1
Q

Duchenne Muscular Dystrophy - Inheritance

A

X-linked Recessive

Affects 1/3000 males

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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

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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.

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4
Q

DMD associated dilated cardiomyopathy

A

early death
dilated cardiomyopathy presenting between 20-40
no skeletal involvement
milder symptoms

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5
Q

Hereditary Neuropathy with Liability to Pressure Paulsy - Inheritance

A

Autosomal Dominant

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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

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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

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8
Q

Osteogenesis Imperfecta Type I - inheritance

A

Autosomal Dominant

1/30,000 to 50,000

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9
Q

Osteogenesis Imperfecta Type I - Clinical Presentation

A

Variable expressivity

Multiple fractures, short stature, adult onset hearing loss, blue sclerae

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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

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11
Q

Charcot Marie Tooth Type 1A - inheritance

A

Autosomal Dominant
fully penetrant
variable expressivity

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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
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13
Q

Charcot Marie Tooth Type 1A - Mechanism

A

Gain of function - demyelination

duplication of PMP22 gene 17p11.2

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14
Q

Osteogenesis Imperfecta Type II, III and IV - Inheritance

A

Autosomal Dominant

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15
Q

Osteogenesis Imperfecta Type II, III and IV - Clinical Presentation

A

More severe form

Brittle bones, increased fractures, blue sclerae

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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.

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17
Q

Huntington Disease - Inheritance

A 
Autosomal Dominant
1/10,000
Anticipation
Early onset - parental
Later onset - maternal
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18
Q

Huntington Disease - Clinical Presentation

A

Progressive neurodegenerative disorder with adult onset motor, cognitive, and psychiatric disturbances
death 15 years after onset

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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.

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20
Q

Myotonic Dystrophy 1 - inheritance

A

Autosomal Dominant

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21
Q

Myotonic Dystrophy 1 - Clinical Presentation

A

Droopy eye, intellectual difficutly, hypotonia

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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

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23
Q

Phenylketouria - inheritance

A

Autosomal Recessive
1/10,000
carrier frequency of 1/50 in Northern European

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24
Q

Phenylketouria - Clinical Presentation

A

Epilepsy, mental retardation, hyperactivity, tremor, gait disorders
High Phe is toxic to CNS

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25
Q

PKU Mechanism

A

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

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26
Q

BH4 mutation

A

PKU mutation

causes decreased levels of serotonin and dopamine as well

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27
Q

PKU treatment

A

Low-Phe diet should be maintained all life.

BH4 deficient should be treated with oral BH4 and supplemented with NTs.

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28
Q

Maternal PKU

A

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.

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29
Q

Newborn Screening of PKU

A

Mass Spec to sort by size and charge.
Compare normal [Phe] to [tyr]
Must be done enough after birth but before CNS is affected.

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30
Q

Alpha1-Antitrypsin Deficiency - Inheritance

A

Autosomal Recessive
More common in N. Europeans
1/2500 affected
1/25 carriers

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31
Q

Alpha1-Antitrypsin Deficiency - Clinical

A

Emphysema, liver cirrhosis/cancer due to accumulation of misfolded alpha1-AT proteins

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32
Q

Alpha1-Antitrypsin Deficiency - Mechanism

A

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.

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33
Q

Alpha1-Antitrypsin Deficiency - Treatment

A

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.

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34
Q

Alpha1-Antitrypsin

A

ATT (SERPINA1)
made in liver
serine protease inhibitor that binds to elastase and inhibits it.

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35
Q

Elastase

A

inhibited by ATT
destroys connected tissue in lung (elastin) to cause emphysema
Made by neutrophils and allows mobilization of lung cells to promote healing.

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36
Q

LTB4

A

secreted from macrophages in lung to make attract neutrophils to make more elastase.

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37
Q

Tay-Sachs Disease - Inheritance

A

Autosomal Recessive
1/360,000
1/3,6000 A Jews

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38
Q

Tay-Sachs Disease - Clinical Presentation

A

Progressive degeneration of CNS, onset at 3-6 months
muscle weakness, loss of voluntary movement, seizures
Eye abnormality/visual loss - cherry red spot

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39
Q

Tay-Sachs Disease - Mechanism

A

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

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40
Q

Sandhoff Disease - Inheritance

A

Autosomal Recessive

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41
Q

Sandhoff Disease - Clinical Presentation

A

Similar to Tay-Sachs, but more severe

Defects in HEXB CH 5 makingbeta subunit in HexA and HexB inative

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42
Q

Sandoff vs. Tay-Sachs

A

TS only has mutation in HexA

S: mutation in HexA and HexB due to defective Beta subunit

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43
Q

AB variant of Tay-Sachs

A

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.

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44
Q

Cystic Fibrosis - Clinical Presentation

A

Salty skin, poor growth and weight gain despite normal food intake
accumulation of thick, sticky mucus, frequent chest infections, coughing

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45
Q

Cystic Fibrosis - Mechanism

A

mutation in CFTR gene (ch 7) needed to regulate sweat, digestive juice and mucus by regulating Na/K channels across epithelial

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46
Q

Hereditary Hemachromatosis - inheritance

A

Autosomal Recessive

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47
Q

Hereditary Hemachromatosis - Clinical Presentation

A

Hepatic cirrhosis in combo with hypopituitarism, cardiomyopathy, diabetes, arthritis, hyperpigmentation
iron overload

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48
Q

Hereditary Hemachromatosis - mechansim

A

mutation in HFE gene on Ch 6

important in iron regulation

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49
Q

Achondroplasia - Inheritance

A

Autosomal Dominant
1/15,000-40,000
80% new mutation (1138)
100% penetrance

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50
Q

Achondroplasia - Clinical Pres

A 
Small stature (4'3" and 4')
Rhizomelic limb shortening, short fingers, genu varum, trident hands, large head, frontal bossing, small foramen magnum
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51
Q

Achondroplasia - Mechanism

A

Gain of Function
Gly380Arg in FGFR3 (CH 4) Gene
Regulates bone growth by limited formation of bone from cartilage.

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52
Q

Retinoblastoma - Inheritance

A

Autosomal Dominance
1/15000
incomplete penetrance

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53
Q

Retinoblastoma - Clinical Presentation

A

malignant tumor of retina
Absence of red retina
strabismus, visual deterioration

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54
Q

Retinoblastoma- Mechanism

A

Mutation in RB1 gene Ch13
RB is a tumor supressor
Loss of function - destabilize or cant associated with enzymes for deacytylation

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55
Q

Neurofibromatosis Type I - Inheritance

A 
Autosomal Dominant
1/3000
50% new mutation rate
Variable expressivity
extreme pleiotropy
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56
Q

Neurofibromatosis Type I - Clinical Presentation

A

Cafe au lait, axillary and inguinal freckling, multiple neurofibromas, lisch nodules (spots.bumps on eyes)

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57
Q

Neurofibromatosis Type I - Mechanism

A

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

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58
Q

Tuberous Sclerosis - inheritance

A 
Autosomal Dominant
1/6000
Variable expressivity
1/3 inherited; 2/3 de novo
fully penetrant
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59
Q

Tuberous Sclerosis - clinical Presentation

A

Hypopigmented patches, angiofibroma, shangreen patch, renal cysts, lymphangiolelomyomatosis, cardiac rhabdomyoma, CNS issues, seizures, ADHD cognitive disorders

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60
Q

Tuberous Sclerosis - mechanism

A

Mutation in TSC1 or TSC2
encode hemartin and tuberin porteins that regulate cell growth and proliferation
on Ch9 and 16
Loss of function mutations

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61
Q

Marfan Syndrome - inheritance

A

AD
1.5000 births
25% new mutation
variable expressivity

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62
Q

Marfan Syndrome - Clinical Presentation

A

connective tissue disorder in aorta, ocular, skeletal, and cardio
aoritc root enlargement, ectopia lentis, scoliosis, pectus excavatum

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63
Q

Marfan - mechanism

A

FBN1 fibrillin - an extracellular matrix proin on Ch15
Negative activity mutation
Severe reduction in #

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64
Q

AD Polycystic Kidney Disease - Inheritance

A

AD

1/1000

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65
Q

AD Polycystic Kidney Disease - Clinical

A

Enlarged kidney with multiple cysts, end stage renal disease, renal cysts in other organs, intracranial aneurysms

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66
Q

AD Polycystic Kidney Disease - mechanism

A

ADPKD-1 mutation on Ch16 on Ch4

Locus heterogeneity

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67
Q

Familial Hypercholesterolemia - inheritance

A

AD

1/500

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68
Q

Familial Hypercholesterolemia - Clinical Presentation

A

High cholesterol
deposits of cholesterol throughout body
premature coronary artery disease

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69
Q

Familial Hypercholesterolemia - mechaism

A

Mutation in gene encoding LDL receptor (cant clear LDL from blood stream)

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70
Q

Fragile X-Syndrome - Inheritance

A

X-linked Dominant
1:2500-4000 in males
1/7000-8000 in males
Anticipatory and maternal bias

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71
Q

Fragile X-Syndrome - Clinical Presentation

A

Mental deficiency, large ears and long face, macroorchism (enlarged testicles), autism like, hand flapping/biting

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72
Q

Fragile X-Syndrome - Mechansim

A

Trinucleotide repeats over 200 in FMR1 in 5’ UTR due to hypermethylation and silencing.

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73
Q

Fragile X-associated Tremor/Ataxia Syndrome - mechanism

A

from fragile X premutation (59-200 CGG repeats) that aren’t hypermethylated but make more RNA

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74
Q

Fragile X-associated Tremor/Ataxia Syndrome - Clinical Presentation

A

Parkinson like features, gait ataxis, premature ovarian failure in women

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75
Q

haplotype effect in Fragile X

A

AGG repeats within CGG to reduce risk

76
Q

what disease has repeats in 5’ UTR

A

Fragile X and FTAXS

77
Q

What disease has repeats in introns

A

Friedrich Ataxis and myotonic dystrophy

78
Q

what disease has repeats in exons

A

Huntington

79
Q

What disease has repeats in 3’ UTR

A

Myotonic Dystrophy 1

80
Q

Hemophilia A - Inheritance

A

x linked recessive
1:4000 males
10% female carriers

81
Q

Hemophilia A - Clinical Presentation

A

Bleeding complications due to decreased clotting

82
Q

Hemophilia A - Mechanism

A

Factor VIII deficiency du to mutation in Chx

can be upplemented by Factor VIII

83
Q

Turner Syndrome - Inheritance

A

45, X
Sex chromosome numerical disorder
Affects 1/2000-1/5000 new born girls

84
Q

Turner Syndrome - Cardio

A

Bicuspid aoritc valve, coarctation, systemic hypertension, prolonged QTc, persistend left SVC

85
Q

Turner Syndrome - Eye

A

Inner canthal folds, Ptosis, Blue sclera

86
Q

Turner Syndrome - skeletal system

A

cubitus valgus, short 4th metacarpal, short stature, shield chest

87
Q

Turner Syndrome - Neck

A

webbed neck, cystic hygroma in utero, low hairline

88
Q

Turner Syndrome - Learning abnormalities

A

difficulty in math, visual spatial skills, low non-verbal skills

89
Q

Turner Syndrome - Endocrine

A

Hypothyroidism, gonadal dysgenesis

90
Q

Turner Syndrome - Physical features

A

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
Q

Challenges associated with Turner Across lifetime

A

1) Infertility
2) stature
3) sexual development
4) concerns regarding health and aging

92
Q

Pitfalls of Turner syndrome

A

1) secret keeping
2) difficulty conveying infertility
3) negative experiences with physician

93
Q

Klinefelter Syndrome - inheritance

A

1:500-1:1000
Sex chromosome non-disjunction
47 XXY

94
Q

Klinefelter Syndrome - Clinical Presentation

A

gonadal dysgenesis/hypogondasim: small testes and decreased body hair, infertility
quiet, wide waist, not broad shoulders.
hypospandias (urethra placement)

95
Q

Klinefelter Syndrome - mechansim

A

Meitoic Non-disjunction
equal distribution between father and mother NDJ
25% are moscaic with increasing X becomes more severe

96
Q

Rett Syndrome - Inheritance

A

X-Dominant
1:10,000 females
95% due to new mutations

97
Q

Rett Syndrome - Clinical Presentation

A

Loss of movement and coordiantion; acquired microcephaly, seizures, abnormal hand mvmt

98
Q

Rett Syndrome - Mechanism

A

mutation in MECP2 (methyl CPg Binding Protein) that is a loss of nerve function

99
Q

Hypophosphatemic Rickets - inheritance

A

X-dominant

1:20,000

100
Q

Hypophosphatemic Rickets - Clinical Presentation

A

Hypoposphatemia (low phosphate levels)

short, bone deformity

101
Q

Hypophosphatemic Rickets - Mechanism

A

Mutation in PHEX gene that regulates fibroblast growth factor
Cant reabsorb phosphate into blood stream

102
Q

Jacob Syndrome - Inheritance

A

Sex Chromosome
47 XYY
1/900

103
Q

Jacob Syndrome - Clinical Presentation

A

usually indistinguishable from normal physically and mentally
Increased risk of behavior or education problems, delayed speech and language, autism spectrum
tall

104
Q

Congenital Adrenal Hyperplasia _ inheritance and clinical presentation

A

Autosomal Recessive 46, XX
1/25,000
Ambiguous genitalia, masculization of females

105
Q

Congenital Adrenal Hyperplasia - Mechanism

A

21-Hydroxylase deficiency so that ACTH is increased and the adrenals are hyperplastic, overproducing androgens

106
Q

Dosage Sensitive Sex Reversal - Inheritance and Clinical Presentation

A

X-linked Recessive

development of ovaries even in presence of SRY

107
Q

Dosage Sensitive Sex Reversal - Mechanism

A

Duplication of DAX1 gene, a nuclear hormone receptor promoting female sex development

108
Q

5 alpha reductase deficiency - inheritance and clinical

A

46, XY
Incomplete phallic dvpt, severe pseudovaginal perineal, ambiguous genitalia that begins normal male development during puberty.

109
Q

5 alpha reductase deficiency - Mechanism

A

Alpha reductase mutation - normally required to convert testosterone to dihydrotestosterone.

110
Q

Androgen Insensitivity Syndrome - Inheritance and clinical Presentation

A

X-linked

mild to severe under virilization

111
Q

Androgen Insensitivity Syndrome - mechanism

A

mutation in androgen receptor so body doesn’t recognize it or respond to testosterone

112
Q

Disorders of SRY Gene - Inheritance and Clinical

A

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
Q

Denys Drash and Frasier Syndrome

A

46 XY sex reversal
chronic kidney dsiease
wilm’s tumor risk
Mechanism: mutation in WT1 (a TF in SRY gene)

114
Q

Non-Syndromic Deafness - Inheritance

A 
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
Q

Non-Syndromic Deafness - Mechanism

A

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
Q

Non-Syndromic Deafness - treatment

A

Newborn screening for detection

hearing aids, cochlear implants, speech and sign language therapy

117
Q

Syndromic Deafness

A

Deafness associated syndromes

General intellecutal-disability, seizures, dysmorphic syndromes

118
Q

Usher Syndrome

A

AR

Deafness with pigmentosa

119
Q

Pendred Syndrome

A

AR

deafness with thryoid goiter

120
Q

Jervell and Lange Nielson Syndrome

A

AR

Arrhythmia or sudden death with deafness

121
Q

Waardenburg Syndrome

A

AD

White forelock with deafness

122
Q

Neurofibromatosis Type II

A

8th Nerve Schwannomas with deafness

123
Q

Fabry Disease - Inheritance and clincial

A

X linked
Neurologic pains, reduced sweating, risk of stroke, progressive renal failure, risk of heart attach, hypertrophy of cardiac tissue

124
Q

Fabry Disease - Mechanism

A

Deficiency of alpha-galactosidase protein misfolding causes accumulation of glycosphingolipids and microvascualr damage

125
Q

Fabry Disease - treatment

A

Chaperone based therapy that helps alpha-galactosidase A fold correctly
ERT

126
Q

Down Syndrome - inheritance

A

Chromosomal abnormality Trisomy 21

1/900

127
Q

Down Syndrome - Clinical Presentation

A

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
Q

Down Syndrome- mechanism

A

95% materal NDJ
3-4% robersonian translocation
1-2% mosaic

129
Q

Trisomy 13 - inheritance and clinical

A

Patau’s
Trisomy 13
growth retardation, intellecutual disability, sloping forehad, misfomed ears, cleft lip/palate, heart defects, urogenital defects

130
Q

Trisomy 18

A

Edward’s syndrome

small for gestation age, microcphaly, clenched hands, overlapping fingers, rocker bottom feet, heart/brain abnomralities

131
Q

Prader-Willi Syndrome - inheritance/mutation

A

Due to imprinting erros on paternal ch15.

1) deletion
2) uniparental disomy of maternal
3) imprinting errors

132
Q

Prader-Willi Syndrome - testing

A

Methylation of Ch15

FISh

133
Q

Prader-Willi Syndrome - phenotype

A

hypotonic, almond shaped eye, lighter pigmentation, undescended testicles, severe feeding problem as infant, but overeating as toddler, leading to obesity and sleep apnea

134
Q

Prader-Willi Syndrome - developmental delays

A

1) motor delay
2) excessive complusion disorder
3) violence from withholding food

135
Q

IMaternally inherited interstitial duplication

A

to make partial trisomy
Duplication of Ch15
Hypotonic, autism
Paternally are phenotypically normal

136
Q

Angelman Syndrome - inheritance and clinical

A

Maternal deletion of 15ch
due to deletion, two copies of pateral allel, imprinting defect, UBE-3A mutation
Seizures, severe intellectual disability, short,

137
Q

WAGR Syndrome - Clinical and mechanism

A

wilms tumor, aniridia, genitourinary anomilies, Intellecutal disability
Interstitial deletion of Ch11p13
can be seen by chromosome analysis or FISH

138
Q

Digeorge Syndrome - clinical and mechanism

A

absent of hypoplastic thymus and parathyroid gland, congenital heart disease
Del 22q11.2

139
Q

Acute Lymphomatic Leukemia - inheritance

A

ALL

Hyperdiploidy

140
Q

Acute Lymphomatic Leukemia - Clinical

A

downs much more likely to develop 20-100x

enlarged spleen, joint or hip pain, anmeia, thrombocytopenia

141
Q

Chronic Myelogenous Leukemia - inheritance/mechanism

A

CML

Bcr-Abl translocation (9:22) in bone marrow

142
Q

Chronic Myelogenous Leukemia - clinical

A

enlarged spleen, joint or hip pain, anmeia, thrombocytopenia

143
Q

Chronic Myelogenous Leukemia - treatment/detection

A

FISH fusion

Gleevec treatment

144
Q

Acute Promyeloid Leukemia - inheritance/mechaism

A

APL/PML
PML-RARA translocation 15:17
viewing Auer rods (cytosolic precip) is diagnostic

145
Q

Acute Promyeloid Leukemia - treatment/detection

A

FIsh Fusion

treatment with Retinoic acid - vitamin A

146
Q

IDIC15

A 
inverted duplicated isochromosome 15
hypotonic with autism
Inverted and euplicated isochorome 15
have extra ch 
maternally inherited
147
Q

Gaucher Disease inheritance

A

Autosomal Recessive
1/50,000
1/450 in AJew

148
Q

Gaucher Disease - clinical

A

hepatosplenomegaly, thrombocytopenia, anemia, joint pain, nose bleeds, CNS issue

149
Q

Gaucher Disease - mechanism

A

Build up of glucocerebrosides in macrophage lysosomes due to lack of glucocerebrosidase function - called gaucher cells that get stuck in liver and spleen

150
Q

Pompe Disease - inheritance and clinical

A

AR

progressive muscle failure, cardiomegaly, hypotonia, respiratory distress, feeding difficulties, failure to thrive

151
Q

Pompe Disease - Mechanism

A

accumulation of glycogen in lysosome due to deficient lysosomal acid alpha-glucosidase enzyme

152
Q

Progeria - inheritance and clinical

A

De novo dominant

premature aging syndrome

153
Q

Progeria Mechanism

A

point mutation in Lamin A/C gene yielding abnormal progerin protein that targets to Nuclear membrane

154
Q

Progeria treamtnet

A

Farnesyl transferase inhibitors reduce progerin sequesteration in nuclear membrane

155
Q

Kearns-Sayre Syndrome - inheritance and clinical

A

mito
1/100,000
Pigmentary retinopathy, difficulty moving eye, atexia, cardic conductance defects, deafness, kidney issues

156
Q

Kearns-Sayre Syndrome mechanism

A

large deletion in mtDNA that removes 12 genes

157
Q

Mitochondria Encephalomyopathy Lactic Acidosis and Stroke like episodes (MELAS) inheritance and clinical

A

Mito I

strokes, muscle weakness, seizures, elevated lactic acidosis in chidlren

158
Q

MERRF

A

Myloclonic epilepsy with Ragged red Fibers
seizures, ataxis, dementia
mutaiton in MT-TK gene

159
Q

Leber Hereditary optic neuropathy

A

Mito inheritance

bilateral subacute vision failure

160
Q

Hb Kempsy

A

Higher binding affinity for O2,but can’t release in tissues.

Leads to increased erythropoietin production and polycythemia

161
Q

Hb Kansas

A

low affinity for O2 to lead to anemia and cyanosis

162
Q

Sickle Cell

A

HbS
AR
Common in AA (10%)
base mutation in codon 6 form Glutamate to Valine to make less soluble when bound to O2.

163
Q

Sickle Cell treatment

A

Byrate to increase fetal Hb and reduce polymerization of bS

164
Q

Sickle Cell testing

A

BetaS has altered restriction site for MstII, so ou get one 1.35 kb fragment instead of two fragments as with BetaA

165
Q

Hemoglobin C

A 
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
Q

HbS or HbC traits

A

heterozygotes with HbA

clinically normal except severe pO2 stress

167
Q

HbSC

A

compound heterzygote

milder anemia than sickle cell

168
Q

HbEE

A

common in Southeast asia
mutation in HbBeta chain
mild hemolytic anemia and mild splenomegaly
Lysine instead of glutamate in codon 26

169
Q

Alpha-Thalassemias

A

deletions in one or both alpha globin genes
make gamma or beta in excess
affects both fetal and adult Hb

170
Q

Hydrops Fetalis

A

–/–
double deletion leads to 0% globin
fetal death because Bart’s Hb is no sufficient to bring to life.
common in Southweat asia

171
Q

Alpha-Thallasemia trait -1

A 
aa/-- 
mild anemia
newborn: F,A, Barts
50% globin
prevantl in Southeast asia
resutls in --/--, a-/--, and aa/--
low or normal-low MCV
172
Q

Alpha-Thallasemia trait -2

A 
a-/a-
mild anemia
50% globin
prevalent in africa, med, asia
creates a-/a-
low or normal low MCV
173
Q

HbH disease

A

a-/–
Severe anmeia
25% globin levels
beta4 Hb

174
Q

Silent carrier for alpha thalassemia

A

aa/a-
50% globin
normal MVC

175
Q

Beta Thalassemia

A

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
Q

Cooley’s Anemia

A 
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
Q

Beta Thalassemia Minor

A

No clinical presentation (very mild)
normal to low MCV
WT/– or WT/Mut

178
Q

Beta Thal Int

A 
AR
2 mildly abnormal genes
mild to moderate anemia
low MCV
sometimes tranfusion dependent
179
Q

Beta+ Thalassemia

A

AR
Most common form 90%
mutation that affects trascription, RNA processing, and stability
some beta made, so HbA is present

180
Q

Beta0 Thalassemia

A

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
Q

Dela-Beta0 thalassemia

A

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
Q

Gamma Thalassemia

A

deletion of gamma

only significant at birth, overcome by 6 months of life

183
Q

Delta Thalassmia

A

deletion of delta globin

not a problem by itself, but when combined with beta more phenotypically present.

184
Q

HPFH

A

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
Q

HPFH methcanism

A

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.

GENETICS M2M (4 decks)

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