General Pathology 5 - Genetic Diseases

Front 1

Definition hereditary?

Back 1

Derived from parents

Front 2

Definition familial?

Back 2

Transmitted in gametes through generations

Front 3

Definition congenital?

Back 3

Present at birth - but not always congenital!

And genetic not always congenital!

Front 4

Example of congenital disease not genetical?

Back 4

Syphilis
Toxoplasmosis

Front 5

Example of genetic disease not congenital?

Back 5

Huntington (3rd- 4th decade)

Front 6

Classification of genetical disorders?

Back 6

1. Polygenic with multifactorial inheritance
2. Monogenic mendelian disorders
3. Chromosomal abberations

Front 7

Name some typical polygenic multifactorial genetic diseases?

Endocrine, heart, psychiatry, neoplasms

With probability of 1st deg rel = 5-10% and 2nd deg =1%

Back 7

- Diabetes mellitus
- Congenital heart diseases
- Some tumors (breast, ovary, colon)
- Hypertension
- Gout
- Schizophrenia

Front 8

Definition gout?

Back 8

Metabolism of uric acid is not working, due to genetic reasons - with accumulation of it in Uric Acid crystals in mostly joints (great toe)

Front 9

What is uric acid metabolised from?

Back 9

Purines of DNA breakdown / turnover

Front 10

what are main symptoms of gout / arthritis uratica?

Back 10

Recurrent arthritis - typically of hallux - with formation of large crystal aggregates called tophi - leading to deformity and destruction of joints!

Front 11

Long term consequence of gout?

Back 11

Renal injury

Front 12

Classification of gout according to cause?

Back 12

1. Primary - 90% - unknown enzymatic defect
2. Secondary - 10%

Front 13

Causes of secondary gout?

Back 13

Hyperuricemia due to:
- Increased nucleic acid turnover (leukemia)
- Chronic renal disease
- Increased uptake (red wine)

Front 14

Classification of gout according to time?

Back 14

Acute and chronic

Front 15

Acute gastritis signs?

Back 15

Sudden intense pain - any joint but mostly hallux.

Reason may be lower temperature - since the crystal are deposited easier there!

Front 16

What is the manifestation of chronic gout?

Back 16

1. Permanent precipitation = tophi of crystals
- Lymphocyts + histocytes (inflamm)

2. Destruction of cartilage
- Fibrosis of synovial membanre
==> Ankylosis of joint

Front 17

Gout rarely precipitate in kidneys, but when it does - what 3 ways may it manifest?

Back 17

1. In medulla / papillae
2. As tophi
3. As kidney stones

Front 18

During fixation of gout biopsy - what is important to remember?

Back 18

Urate cyrstals are soluble in water - so you must use absolute alcohol!

Front 19

Typical locations for urate crystal precipitation?

Back 19

- Edges of joints
- Olecranon bursa
- Prepatellar bursa
- Auricle

Front 20

Typical gout patient?

Back 20

1. Fat
2. Arteriosclerosis
3. Possible hypertension

Front 21

What are the 3 stages of clinical presentation of gout?

Back 21

1. Asymptomatic hyperuricemia
2. Sudden attack of arthritis (days-weeks) with silent periods (months-years)
3. Chronic stages with :
- Tophi
- Ankylosis
- Chronic renal failure (20%)

Front 22

What are the most famous autosomal dominant disorders?

Back 22

- Familial hypercholesterolemia
- Huntingtons
- NF 1/2
- Marfan syndrome
- Ehler-Danlos syndrome
- HNPCC

Front 23

Definition familial hypercholesterolemia?

Back 23

Familial condition with high plasma cholesterol and early development of atherosclerosis

Front 24

What mutation have occurred in familial hypercholesterolemia?

Back 24

Mutation of gene encoding LDL-receptor of liver - which is responsible for uptaking 70% of it!

Front 25

How is difference in plasma cholesterol in homozygotes & heterozygotes in f.hyperchol?

Back 25

AA = 5x elevation
Aa = 2x elevation

Front 26

How is difference in symptoms in AA / Aa in fam-hyperchol?

Back 26

AA = Xanthomas in childhood, death by 15y due to MI
Aa = Asymptomatic in childhood - xanthomas along tendon sheets & coronary atherosclerosis :(

Front 27

Definition Marfan syndrome?

Back 27

Genetic disorder of CT, due to abnormal fibrillin protein secreted by fibroblasts - which is a normal part of ECM.

This leads to impairment of CT and elastic tissue, to less firmness

Front 28

What are the 3 main systems that Marfan syndrome manifest in?

Back 28

1. Skeleton / CT
2. Eyes
3. Cardiovascular

Front 29

Typical skeletal manifestations of Marfan syndrome?

Back 29

- Long slender habitus
- Long fingers (arachnodactyly)
- Very high gothic palate
- Hyperextensibility of joints
- Spinal & chest deformities

Abraham Lincoln??

Front 30

What are the ocular manifestations of Marfan syndrome?

Back 30

Usually a dislocation or subluxation of the lens - due to weakness of suspensory ligaments

Front 31

What are the cardiovascular manifestations of Marfan syndrome?

Back 31

1. Weakness of fibers in t.media of aorta --> Aneurysm or dissection or even rupture (40%)

2. Aortic valve incompetence (dilation)

3. Floppy mitral / tricuspid valve

Front 32

Definition Ehler-Danlos syndrome?

Back 32

A inherited disorder of CT, affecting skin, joints and blood vessel walls

Front 33

What is the genetic defect in Ehler-Danlos syndrome?

Back 33

Genetic defect of collagen fibrils - several types… This can be both autosomal dominant & recessive!

Front 34

What are symptoms of Ehler-Danlos syndrome?

Back 34

1. Skin hyperextensibility
2. Joint hypermobility
3. Joint dislocations
4. Rupture of large vessels

Front 35

Characteristics of autosomal recessive disorders?

Back 35

aa:
- Only homozygotes affected
- Heterozygotes are carriers
- 25% of descendants are affected
- High probability in consanguioneous marriages
- Often enzymatic defect

Front 36

How many births does CF occur in?

Back 36

1 in 2000 - most common lethal genetic disease

Front 37

What is the mechanism behind CF?

Back 37

Defective transport of chloride and sodium over epithelium - leading to very viscous secretinos in all exxocrine glands, leading to blockage of:
- airways
- Pancreatic ducts (thus name)
- BIliary ducts

Front 38

Most important clinical manifestations of CF?

Back 38

1. Recurrent respiratory infections
2. Pancreatic insufficiency
--> Malabsorption syndrome
----> Hypovitaminosis of fat soluble vit (ADEK)
3. High sodium in sweat - salty baby syndrome

Front 39

Definition phenylketonuria?

Back 39

Inherited inability to metabolize phenylalanine to tyrosine - which if left untreated - lead to brain and nerve damage

Front 40

How does phenylketonuria lead to brain damage?

Back 40

It impairs brain development - at 6 months after birth one have severe mental retardation with IQ below 50

Front 41

Any physical symptoms seen in phenylketonuria?

Back 41

Yes, melanin is derived from tyrosine, so there is lower pigmentation of skin and hair

Front 42

Patient with PKU have kept strict diet until grown up age - is it all no danger anymore?

Back 42

If man - yes.

If women - no, since phenylalanine can transfer across placenta - and cause mental retardation of child

Called 'maternal PKU'

Front 43

Definition galactosemia?

Back 43

Inherited disorder where an enzyme needed for metabolization of galactose (from lactose --> gal + glu) is lacking, and galactose is accumulating in blood

They must keep away from galactose!!!

Front 44

Typical symptomatic locations of galactosemia?

You think about milk
You see milk
You drink milk

Back 44

1. Brain
2. Eyes
3. Liver

Front 45

Cerebral manifestation of galactosemia?

Back 45

1. Loss of neurons
2. Gliosis
3. Edema

Front 46

Definition gliosis?

Back 46

Reactive change to damage to CNS - with hypertrophy of glial cells including astrocytes, microglia, oligodendrocytes - and leading to a glial scar in its most extreme form

Front 47

Ocular manifestations of galactosemia?

Back 47

Blurring (cataracts) and opacification (progressive cloudiness)

Front 48

Liver manifestations of galactosemia?

Back 48

1. Fatty change
2. Fibrosis
3. Cirrhosis

= Hepatomegaly!

Front 49

Early symptoms of galactosemia?

Back 49

Vomiting
Diarrhea
Jaundice
Hepatomegaly

Front 50

Late symptoms of galactosemia?

Back 50

Clouding of lens
Mental retardation

Front 51

Definition glycogenosis?

Back 51

Many different inherited disorders of glycogen meteabolism

Front 52

What are the 3 most important (of 12) glycogenoses? (glycogen storage diseases)

Back 52

I - Von Gierke
II - Pompe
III - McArdle

Front 53

In biopsy of liver e.g. - how to stain for glycogenoses?

Back 53

1. PAS
2. Best carmine

Front 54

Definition lysosomal storage disease?

Back 54

Group of about 50 diseases with defects in lysosomal enzymes, leading to storage of insoluble metabolites in lysosomes

Front 55

Name the 4 most important lysosomal storage diseases?

Back 55

1. Niemann-Pick
2. Tay-Sach
3. Gaucher
4. Mucopolysaccharidoses

Front 56

Which lysosomal disorder is more common in Ashkenazi jews?

Back 56

Spingolipidoses:
- Niemann pick
- Tay sach
- Gaucher

And a few more (Krabbe, Fabry)

Front 57

Definition mucopolysaccharidosis?

Back 57

Any disorder of mucopolysaccharides leading to increased accumulation of them in tissues

Front 58

Symptoms of mucopolysaccharidoses?

Back 58

1. Gargoylism (dwarf like, deformities of head)
2. Corneal clouding
3. Joint stiffness
4. Mental retardation

Front 59

If mother is carrier - how will children be affected in X-linked disease?

Back 59

50% sons affected (
50% daughters carriers

Front 60

If father is affected with X-linked disease - how will children be affected?

Back 60

Sons are healthy (give the Y chromosome)
All daughters are carriers

Front 61

Most important examples of X-linked diseases?

Back 61

- Hemophilia A
- Hemophilia B
- Muscle dystrophy
- Sickle cell anemia
- Thalassemia
- Hunter's mucopolysaccharidosis

Front 62

Hemophilia A is defect of which coagulation factor?

Back 62

VIII (Aight)

Front 63

Hemophilia B is defect of which coagulation factor?

Back 63

IX (Bnine)

Front 64

Definition cytogenic disorder?

Back 64

A disorder with a chromosomal abberation - a difference in number of structure of chromosomes, either the autosomes or sex chromosomes

Front 65

Which abnormalities can we divide chromosomal abberations into?

Back 65

1. Numerical
2. Structural

Front 66

How may we study the chromosomes?

Back 66

1. Arrest cell in metaphase with colchicin
2. Stain by Giemsa
3. Photograph them and karyotype them

Front 67

How many chromosomes? And autosomes?

Back 67

23 pairs of chromosomes
22 pairs of autosomes
1 pair of sex chromosomes (XX, XY)

Front 68

Frequency of cytogenetic disorders?

Back 68

Quite frequent! Up to 1:160 births - and 50% of all spontaneous abortions (since a lot, especially the autosome abberations, are not compatible with life)

Front 69

What is the potential numerical chromosome abnormalities?

Back 69

Euploidy
Polyploidy
Aneuoploidy
Trisomy
Monosomy
Sex chromosomal

Front 70

Definition ploidy?

Back 70

The number of chromosomes in nucleus of biological cell

Front 71

Euploidy?

Back 71

Normal number of chromosomes = 46 (2n)

Front 72

Polyploidy? Compatible with life?

Back 72

3n or 4n - leads to spontaneous abortion

Front 73

Definition aneuploidy?

Back 73

When the chromosome number is not exactly right - we have:
- Trisomy
- Polysomy
- Monosomy
- Nullsomy

Front 74

Trisomy (2n+1)? Compatible with life?

Back 74

47 chromosomes - yes life compatible

Front 75

Monosomy (2n-1)? Compatible with life?

Back 75

45 chromocomes - not life compatible

Front 76

Sex chromosomal abberation - life compatible?

Back 76

No

Front 77

Definition structural abnormalities?

Examples?

Back 77

Breakage of chromosome followed by rearrangement:

- Deletion
- Translocation

Front 78

Most dangerous - loss or gain of chromosomes?

Back 78

Loss

Front 79

Most dangerous - sex or autosomal chromosome abberations?

Back 79

Autosomal

Front 80

Most common autosomal chromosome disorders compatible with life?

Back 80

1. Trisomy 21 - Down's syndrome (1:700 births!)
2. Trisomy 18 - Edwards syndrome

Front 81

Risk factors of trisomy 21?

Back 81

High maternal age (>45 1:25) - most frequently the abnormality is in the ovum, since it's under long time influence of environment

Front 82

Main clinical symptoms of Down's syndrome?

Back 82

1. Mental retardation (IQ <50)
2. Flat face
3. Congenital heart defects
4. Transverse line in hand
5. Increased risk of leukemias
6. Decreased tonus of skeletal muscles & joint hypermobility

Front 83

CoD trisomy 21?

Back 83

Cardiac complications - 40% before 10Y

Front 84

What are the spectrum of sex chromosomal disorders?

Back 84

From 45 (XO) --> 49 (XXXXY)

Front 85

Definition Klinefelter syndrome?

Back 85

X-linked chromosomal abberation of 47 XXY in men leading to
- Small testes
- Long legs
- Enlarged breast
- Mental retardation

Xtra X from either of the parents

Front 86

Frequency Klinefelter syndrome?

Back 86

1:1000

Front 87

Definition Turner syndrome?

Back 87

X-linked chromosomal syndrome in females where they do not have the extra X - 45,X0

Front 88

Manifestations of Turner syndrome?

Back 88

- Gonadal dysfunction (non-working ovaries)
--> Amenorrhea & sterility

- Congenital heart disease
- Thick neck & broad chest
- Short stature (growth retardation)

Front 89

Frequency of Turner syndrome in female?

Back 89

1:3000

Front 90

How to do prenatal diagnostics?

Back 90

1. Amniocentesis
2. Cytogenetic analysis
- Karyotype (Down)
3. Biochemical activity of some enzymes
- Tay Sach
4. Various gene analysis with PCR
- CF gene
5. Sex of fetus
- X-linked : Hemophilia

Front 91

Definition congenital malformations?

Back 91

Structural defects present at birth

Front 92

Which viral infections may cause congenital malformations?

Back 92

- Rubella
- CMV

Front 93

Which bacterial infections may cause congenital malformations?

Back 93

- Syphilis
- HIV
- Toxoplasmosis

Front 94

Which congenital disorders are transcervical?

Back 94

HSV (herpes simplex)
HIV

Front 95

Which congenital disorders are transplacental?

Back 95

Syphilis
Toxoplasmosis
Rubella (german measles)
CMV

Front 96

Below what weight is a high risk premature baby?

Back 96

Below 2500 g

Front 97

Most typical prematurity diseases / deaths?

Back 97

1. Intracerebral bleeding
2. Infant RDS
3. SIDS
4. Erythroblastosis fetalis

Front 98

Cause of intracerebral bleeding in prematurity?

Back 98

Immature vessels in BG

Front 99

SIDS?

Back 99

Sudden infant death syndrome