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SMUSPG-PHY1 > Genetic Disorders > Flashcards

Genetic Disorders Flashcards

1
Q

What genetic factors contribute to birth defects

A

permanent genomic change
1] Single-gene defect,
2] chromosomal aberrations,
3] multi-factorial inheritance

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2
Q

What environmental factors affect fetal development

A

Maternal disease
nutritional status, Gestational diabetes, drug and alcohol use

Intrauterine- rare, fetal crowding, positioning, or entanglement of fetal parts

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3
Q

What is dorsum of foot pressed against medial aspect of calf?

A

congenital malformation
S/S-dorsiflexed onto shin; arch formed in the opposite direction/inverted like rocking horse.
TX- massage, cement-casted, x18mo, then surgery

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4
Q

Which inheritance pattern causes the majority of single gene disorders?

A

Autosomal Dominant,
>50% or majority

AD: Variable onset delayed into adulthood
AD: from affected parent, sporadic cases possible.
AD: Incomplete penetrance with variable expression
AD: ***structural protein or receptor
AD: Mutation of one allele

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5
Q

Which inheritance pattern are of sex linked disorder?

A

X-Linked Recessive

Y-linked inheritance-impairs spermatogenesis, therefore not transmitted

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6
Q

Which inheritance pattern causes dysfunction in enzymes?

A

Autosomal Recessive
AR: Early uniform onset (infancy/childhood)
AR: Mutations 2 mutant alleles, may “skip” generations
AR: Complete penetrance
AR: enzyme protein

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7
Q

Describe penetrance

A

extent to which the properties controlled by a gene, its phenotype, will be expressed.
all or nothing event.

Huntington Disease-95% penetrance
5% with the dominant allele DONT acquire the disease 95% with the dominant allele WILL acquire

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8
Q

What type of inheritance pattern is Marfan’s syndrome?

A

Autosomal Dominant
Fibrillin I gene mutation on chromosome 15 (FBN1)
microfibrils providing strength and structure and support for growth factors

CP- 1] Tall, thin build with abnormally long arms and legs, 2] Hyperextensible joints,
3] Pectus excavatum: sternal collapse
4] Pectus carinatum: narrow ribs collapse
5] Arachnodactyly (spider like finger)

Ectopia lentis - bilateral subluxation of the lens,

CV risk-1] Cystic medial necrosis →dissecting aortic aneurysm - common cause of death,
2] Dilation of aortic ring → aortic valve insufficiency,
3] Mitral valve prolapse

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9
Q

Describe neurofibromatosis

A

Autosomal Dominant, 50% inherited from parent, 50% from NEW mutations (due to sporadic phenomenon)

NF-1 tumor suppressor gene on chromosome 17,
inhibits excessive growth

Neurogenic, Schwann cell/PNS tumors; comes in 2 types, 1] von Recklinghausen-90% of cases
2] bilateral acoustic neurofibromatosis, involves the Acoustic nerve

CP-
1] Multiple neurofibromas
2] Café-au-lait spots,
3] Iris hamartoma (Lish nodule) - little vascular formations 4] scoliosis

Risk- 3% transform to malignancy, meningioma and pheochromocytoma

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10
Q

What is the cause of neurofibromatosis type II

A

mutation in the NF-2 on chromosome 22 with unknown function
Who- rare, African Americans

1] Multiple neurofibromas,
2] affects acoustic nerve
3] Café-au-lait spots,

DX- genetic test

Risk- meningioma and pheochromocytoma

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11
Q

Describe the pathophysiology of NF-1 mutation

A

NF-1 is a tumor suppressor gene which functions as a GAP protein that inactivates RAS,
Mutation in NF-1- RAS activated

RAS- a G-protein, growth factor receptor on the plasma membrane relaying a signal to cell growth, RAS is a proto-oncogene

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12
Q

What must be present for tumor formation of neurofibromatosis?

A

2 mutated copies, tumors occur later with acquisition of genetic damage, becomes less able to overcome genetic mutations

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13
Q

Describe why Dolly, the cloned sheep, ended up with tumors

A

adult dna cloned means you clone the mutations, these clones ended up with a lot of tumors

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14
Q

Describe albanism

A

AR
absense of pigment in skin, eyes, hair

Carribean island – Kuna with high rate of Albinism

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15
Q

Describe ataxia telangiectsia

A

AR

Progressive degeneration of nervous system

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16
Q

Describe bloom syndrome

A

AR

dwarfism, skin rash, increased cancer rate

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17
Q

Describe phenylketouria (PKU)

A

Autosomal Recessive
Excess accumulation of phenylalanine in blood due to no PAH ENZYME
Mutation in a gene for enzyme phenylalanine hydroxylase which converts phenylalanine to tyrosine

Ireland-AR is more prevalent in communities that are homogenized/inbred or island. phenylalanine may protect against ochratoxin A, fungi, associated with spontaneous abortions

CP-1] brain damage, mental retardation, seizures by 6 months of age,
2] Accumulation of phenylacetate → mousy or musty sweat and urine odor,
3] Lack of tyrosine → limited pigmentation,
4] enhanced reflexes- DDX newborns
Low set ears, rounded eyes, protuberent tongue

TX- low phenylalanine/protein diet

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18
Q

Describe sickle cell anemia and thalassemia

A

AR
Abnormal hemoglobin, blood vessel blockage, early death

Improper hemoglobin production
from mild to fatal,
Asians and Mediterreans

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19
Q

Describe pathophysiology of Tay Sachs

A

Missing Hexosaminidase A, lysosomal enzyme, Gangliosidoses,
substances from nervous tissue membranes deposited in neurons of CNS, retina.
amaurotic familial idiocy
Ashkenazi Jews (homogenized population)

1] Progressive weakness, flaccidity, decreased attentiveness at 6-10 months,
2] cherry red spot in macula, blindness (amaurosis),
3] severe cognitive impaired seizure disorder,
4] death <3-4 years old

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20
Q

Describe the pattern of X-linkage recessive

A

defective alleles on X chromosome, 50% chance of transmission by affected female. Affected males transmit to all daughters (XX), boy (XY)

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21
Q

Describe the pathophysiology of Fragile X

A

Associated with a fragile site on the X chromosome where the chromatin fails to condense during mitosis. CGG repeat mutation (hundreds to thousands of times). Mutation in the FMR-1 gene (familiar mental retardation) which is on X chromosome

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22
Q

Describe the presentation of Fragile X

A

Mental retardation, Elongated face with large jaw, Large everted ears, hyperextensible joints, short temper, irritable, Macro-orchidism (large testes)

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23
Q

Describe the morbidity of cystic fibrosis (mucoviscidosis)

A

1] Most common lethal genetic disorder in Caucasians

2] Most common cause of death is pulmonary infection,

3] Mean survival is 30 years

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24
Q

What does cystic fibrosis affect?

A 
1] sweat glands, 
2] Mucus glands, 
3] Lung and Bronchial tube, 
4] Pancreas, 
5] Male reproductive system (sterile), 
6] Liver,
 7] GI tract
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25
Q

What is the pathophysiology of cystic fibrosis

A

Mutation of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein
Reduces fluid in glandular secretions when mutated, mucus is thicker and more viscous
resulting in obstruction of exocrine gland ducts.

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26
Q

Where is the CFTR gene located?

A

chromosome 7

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27
Q

What is the genotypic mutation that results in cystic fibrosis?

A

70%, deletion of the three base pairs that codes for phenylalanine at position 508 is the cause.
mutation causes the CFTR protein to fold improperly causing it to be destroyed in the ER before reaching to cell membrane

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28
Q

What is the gold standard test for cystic fibrosis

A

**Sweat chloride test,
CF patients have INC {CL] in sweat and tears,
d/t impaired reabsorption by the sweat ducts

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29
Q

Why are cystic fibrosis patients more prone to pulmonary infections?

A

1] Common Infection with P. aeruginosa and S. aureus,
2] Chronic bronchitis,
3] Bronchiectasis (localized, irreversible dilatation of part of the bronchial tree)

NORMAL Mucus traps pathogens
sends them out via mucociliary escalator
keeps away from alveoli;

CF ends up trapping and holding it in the lungs, promoting infection

30
Q

Describe how cystic fibrosis affects the pancreas

A

1] Plugging pancreatic ducts → atrophy and fibrosis -> Pancreatic insufficiency → Fat and fat-soluble malabsorption -> Malodorous steatorrhea,

2] Unable to absorb ADEK vitamins well -> vitamin deficiency

31
Q

Describe how cystic fibrosis affects organs?

A

Male-Obstruct vas deferens and epididymis → male infertility

Liver-Obstruct biliary canaliculi → biliary cirrhosis

Small intestinal obstruction (meconium ileus)

32
Q

Where is glycogen synthesis and degradation primarily occur?

A

liver- inc glucose
skeletal muscle-energy
Cardiac muscle and kidney, store glycogen

33
Q

What disease causes glycogen accumulation in liver, heart and muscle )

A

Cori diseases
glycogen storage disease

Lack of alpha-1,6-glucosidase (debranching enzyme),
Milder hypoglycemia, liver enlargement

34
Q

Describe what hypoglycemia can lead to

A

1] Lactic acidosis,
2] hyperlipidemia,
3] hyperuricemia

35
Q

What is the most common form of lysosomal storage disease?

A

Gaucher
Type I-MC
type II and type III-CNS involvement

Glucocerebrosidase is missing, resulting in accumulation of Glucocerebroside, in the lysosomes (enzyme storage) of the reticuloendothelial system

1] Gaucher’s cells-enlarged macrophage with tissue paper-like cytoplasm
2] Hepatosplenomegal,
3] Hypersplenism: Pancytopenia or thrombocytopenia,
4] Erosion of bones, fracture

36
Q

What is a deficiency in the lysosomal enzymes required for the degradation of mucopolysaccharides?

A

Mucopolysaccharidosis (MPS)

(glycosaminoglycans). heparan sulfate and dermatan sulfate – prevalent in joints

Two types
Hurler syndrome: death by 10 years, autosomal recessive

Hunter syndrome: milder, X linked recessive

1] Mental retardation, 
2] Cloudy cornea, 
3] Hepatosplenomegaly, 
4] Coarse facial features (gargoyle-like feature), 
5] other skeletal deformities, 
6] Coronary artery abnormality
37
Q

Describe the synthesis of cholesterol and Enzyme needed for synthesis

A

cells derive from LDL or HDL,
some cholesterol may be synthesized de novo (new) occurs in the liver from acetyl CoA in the cytoplasm or diet

HMG-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate limiting enzyme

38
Q

What factors affect HMG-CoA reductase?

A

1] cholesterol represses, increase degradation of the enzyme
2] glucagon inhibit this enzyme.

  1. INSULIN activates - inc cholesterol
39
Q

What is the cause of familiar hypercholesterolemia

A

Mutation-LDL receptor on chromosome 19
1 in 500 people, MC-inherited disorder

1] Anomalies of receptors for LDL l/t dec. transport of LDL into cells -> Inc. level of circulating cholesterol → early atherosclerosis

2] Loss of feedback inhibition of HMG-CoA reductase,

3] Increased phagocytosis of LDL by macrophage

40
Q

What are yellow lesions filled with lipid-laden macrophage?

A

xanthoma

41
Q

Describe the presentation of type I hyperlipidemia

A

Type I: autosomal recessive, rare,
elevated triglycerides, chylomicrons

1] Excess TG deposit in liver, skin and pancreas, 
2] Red-orange eruptive xanthomas, 
3] Fatty liver
4] Acute pancreatitis
5] Abdominal pain after fatty meal
42
Q

Describe the presentation of type IIa hyperlipidemia

A

Type IIa: autosomal dominant
type IIa: elevated cholesterol, LDL

1] ABN receptors for LDL,
2] High risk of atherosclerosis and CAD
3] Homozygous condition usually death < 20 years,
4] Xanthomas elbows, tendon, corneal arcus

43
Q

What is the presentation of hypertriglyceridemia due to diabetes, alcoholism and G6PD deficiency?

A

increased VLDL and Chylomicrons.

44
Q

Describe

A

hemophilia A-lack of clotting factor VIII

hemophilia B- “Christmas disease”, lack of clotting factor IX

45
Q

Describe the cause of Huntington’s disease

A

CAG repeat mutation, caused by Mutation in the Huntington gene that produces abnormal protein, (huntinton) which is neurotoxic leading to atrophy of caudate nucleus

46
Q

Describe the presentation of Huntington’s disease

A

1] Early onset of progressive dementia (age 20-50), 2] Choreiform movement

47
Q

Describe the cause of Duchenne muscular dystrophy

A

rapidly Progressive weakness and loss of muscle tissue
1] X-linked recessive-MC, Duchenne muscular dystrophy,
2] Autosomal

Gene encodes for dystrophin which functions to Stabilizes cell membrane during the stress of muscle contraction

48
Q

Wha is difference btwn polygenic vs.

A

determined by two or more genes
vs
two or more genes and environment

49
Q

What are examples of multifactorial traits

A 
1] Cleft lip or palate, 
2] Clubfoot, 
3] Congenital dislocation of the hip, 
4] Congenital heart disease,
5] Pyloric stenosis, 
6] Urinary tract malformation
50
Q

What are the types of chromosomal disorders

A

1] Alterations in chromosome number or structure

51
Q

Define Polyploidy

A

a chromosome number that is a multiple of the normal haploid set like triploid

52
Q

Define Aneuploidy

A

a chromosomal number that varies by something less than a set

53
Q

Define Monosomy

A

one member of a homologous pair (2n-1)

54
Q

Define Trisomy

A

three copies of a single chromosome (2n+1)
Only trisomies 8, 13, 18, and 21 result in live birth,
8,
13-Patau syndrome (47,+13)
18-Edwards syndrome (47,+18)
21-Down syndrome (47,+21)

55
Q

Describe the lethalty of autosomal monosomy and trisomy

A

Autosomal monosomy is a lethal condition; Autosomal trisomy most of the time are lethal

56
Q

Describe risk factor for Patau syndrome

A 
Parental age  risk factor 
1] Mean survival time 1 month, 
2] Mental retardation, 
3] Cleft lip and/or palate, 
4] Cardiac defect, 
5] Renal abnormalities, 
6] Microcephaly, 
7] Polydactyly
57
Q

Describe risk factor for Edwards syndrome

A

maternal age is a risk factor
80% of all trisomy 18 are female

1] Small at birth and grow slowly, 
2] Mental retardation, 
3] Low set ears, 
4] Micrognathia (small teeth),
 5] Congenital heart disease, 
6] Overlapping flexed fingers, 
7] Rocker-bottom feet, 
8] 2-4 months
58
Q

Describe the presentation of rocker-bottom feet

A

bones are arranged in a different way and this makes the underside of the foot convex in the middle

59
Q

What was the Most common first chromosomal abnormality discovered in humans (1959)

A 
Down Syndrome (47,+21)
 1/900 live births,  
Leading cause of inherited mental retardation and heart defects in US 
40% chance of congenital heart defects

only autosomal trisomy that allows survival into adulthood

1] Wide flat face,
2] Broad short neck,
3] Low-bridged nose,
4] Epicanthal folds-skin folds in the inner corner of the eyes
5] Brushfield spots-spots on the irises (speckled appearance)
6] Palmar (simian) crease-a single crease
7] thick, furrowed tongues

60
Q

Describe clinical findings regarding of the internal organs of Down syndrome

A

1] Congenital heart disease,
2] Duodenal atresia (“double-bubble sign”),
3] Hirschsprung disease-a congenital aganglionic megacolon: no movement causes bowel obstruction →
4] I risk of Acute lymphocytic leukemia,
5] Irisk of Alzheimer disease by 40

61
Q

What are the risk factors for autosomal trisomy

A

1] Advanced maternal age,
2] Under age 25, 1 in 2000,
3] Risk after 35 years of age: exponential risk

62
Q

What is the chromosome aneuploidly of Turner’s syndrome

A

45, X, with no barr body present
only compatible w/ life

***female hypogonadism

1] Females; short, wide chest,
 2] Cystic hygroma, 
3] Hypothyroidism, 
4] Puffiness of hands and feet, 
***5] No mental dysfunction
CV
1] Preductal coarctation of the aorta, 
2] Bicuspid aortic valve

98% of all fetuses spontaneously aborted (hydrops fetalis) complete absence of an X chromosome is lethal

63
Q

What is the chromosome aneuploidly of XYY syndrome

A

47, XYY

64
Q

What is the function of the second X chromosome

A

The second X chromosome is required for normal development of ovary and oogenesis

1] rudimentary ovaries (atrophic “streaked” ovaries) = gonadal dysgenesia,
2] Primary amenorrhea,
3] Infertility,
4] Failure to develop secondary sex characteristic

65
Q

Describe genetic presentation of Klinefelter Syndrome

A

aneuploidly 47, X-X-Y, other forms are 48, XXYY, 48, XXXY and 49, XXXXY
male hypogonadism: LH and FSH increase and Testosterone decreases

The more X, the more chance of mental retardation
 after puberty: 
1] Testicular atrophy, 
2] Infertility due to azoospermia,
 3] Eunuchoid body habitus, 
4] High pitched voice,
 5] Female distribution of hair,
6] Gynecomastia, 
7]  mental dysfunction
66
Q

Describe presentation of XYY syndrome

A

1] Above average in height,

2] No possible antisocial behavior

67
Q

Describe triploidy

A

triploidy- MC polyploidy
1] Three sets of chromosomes (69),
2] 1% conceptions are triploid but 99% die before birth

68
Q

Describe genomic presentation of Cri du Chat syndrome

A

45 xx, 5p- or 45 xy, 5p-

1] High pitched cat like cry, 2] Mental retardation, 3] Congenital heart defect, 4] Microcephaly

69
Q

Give examples of disorders that involve chromosome microdeletion

A

Deletion of 1] 13q14: the retinoblastoma gene,

2] 11q13: the Wilms tumor gene

70
Q

Define Tertagenic agents

A

agents that produce abnormalities during embryonic or fetal development
1] Radiation,
2] Chemicals and drugs,
3] Infectious agents

1] Fetal alcohol syndrome,
2] Cocaine babies,
3] Folic acid deficiency

SMUSPG-PHY1 (15 decks)

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