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Flashcards in Common Genetic Disorders Deck (25)
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1

List the 3 main symptoms of Huntington's disease.

What is the age of onset for Huntington's?

Progressive chorea
Dementia
Psychiatric symptoms

Onset: 30-50 yo

2

What sort of inheritance does Huntington's disease follow?

Describe the genetic basis of Huntington's disease. (3)

Autosomal dominant with genetic anticipation

GENETIC BASIS:
1. Mutation on Huntington gene on chromosome 4

2. Trinucleotide disorder: caused by CAG repeats
a. Up to 35 repeats: not affected
b. 35-39 repeats: partial penetrance
c. 45+ repeats: severely affected (NOTE: repeats expand via meiosis, causing genetic anticipation)

3. CAG repeats code for a polyglutamine (polyQ) tract
a. The polyQ tract makes protein molecules "sticky"
b. This makes the protein molecules aggregate and become insoluble
c. These protein aggregates are neurotoxic

3

Describe DNA testing for Huntington's disease. Consider:

a) Who would you test?
b) Would you test children with affected relatives?
c) Can this affect life insurance?

Who for?
-Presymptomatic/predictive tests for people with affected relatives

Would you test children?
-No: because this is adult onset; therefore no benefit of knowing test result as a child

Life insurance:
-Insurance companies CAN ask for positive results, therefore can affect life insurance

4

List the 4 main symptoms of myotonic dystrophy.

What is the age of onset for myotonic dystrophy?

Progressive muscle weakness
Myotonia
Cataracts
Diabetes

Age of onset: adult

5

What sort of inheritance does myotonic dystrophy follow?

Describe the genetic basis of myotonic dystrophy. (4)

Autosomal dominant inheritance with genetic anticipation

GENETIC BASIS:
1. Trinucleotide repeat disorder: CTG repeat in the 3' region of the DMPK gene
a. This area is transcribed but not translated (i.e. only forms mRNA, not protein)
b. 50+ repeats: severely affected

2. Normally, splicing factors (e.g. muscleblind proteins) are proteins needed to splice other genes

3. Splicing factors are mopped up (sequestered) by abnormal DMPK mRNA, so that other genes cannot be spliced properly
a. Therefore the genes can't function properly

4. This cause indirect toxic effects on other genes, e.g.
a. CLCN1 gene: chloride ion channel (causing myotonia)
b. Insulin receptors (causing diabetes)

6

Describe DNA testing for myotonic dystrophy. Consider:

a) Who would you test?
b) Would you test children with affected relatives?
c) Can this affect life insurance?

Who for?
-People with affected relatives

Would you test children?
-No: it's an adult onset disease, therefore no benefit of knowing in childhood

Life insurance:
-No effect: companies not allowed to ask for test results

7

List the 3 main symptoms of cystic fibrosis.

What is the age of onset for CF?

Abnormally thick sputum/other bodily secretions
Recurrent lung infections
Exocrine pancreatic insufficiency

Age of onset: childhood

8

What type of inheritance does CF show?

Describe the genetic basis of CF. (3)

Autosomal recessive inheritance

GENETIC BASIS:
1. Mutation of the CFTR gene (thousands possible); most commonly: F508del (i.e. deletion of phenylalanine (f) at position 508)
a. This prevents normal protein folding and insertion into the plasma membrane
b. Therefore the chloride ion channel can't function properly

2. This means that chloride (and therefore water) cannot leave the cells
a. This causes secretions with increased thickness

3. This results in recurrent lung infections and pancreatic insufficiency, among other problems

9

Describe DNA testing for CF. Consider:

a) Who would you test?
b) Would you test children?
c) How would you calculate risk of CF on family trees?

For who?
-Cascade testing: systematic testing of family members of an affected individual to identify other affected individuals and carriers
-Newborn CF screening

Would you test children?
-Yes

How would you calculate risk of parents having an affected child?
-Although there's a 1 in 20 risk of an individual being a carrier, there is only a TINY risk of BOTH parents being carriers
-Therefore this risk isn't included in calculations, and population risk of CF is used

10

List 7 symptoms of neurofibromatosis 1.

Cafe au lait spots/macules
Neurofibromas
Short stature
Macrocephaly
Learning difficulties
Lisch nodules in the eye (2+)
Brain tumours

11

List 6 (rare) complications of neurofibromatosis 1.

Hypertension
Scoliosis
Tibia fractures
Phaeochromocytoma
Sarcoma
Optic pathway glioma

12

What sort of inheritance does neurofibromatosis type 1 follow?

Describe the genetic basis of NF type 1. (2)

Autosomal dominant with variable expression

GENETIC BASIS:
1. NF1 gene codes for neurofibronin, which normally inhibits RAS proteins in the RAS signalling pathways
a. Therefore inhibits the cell cycle

2. Therefore mutation in NF1 causes continuous activation of the cell cycle
a. This leads to several types of cancer

13

Describe DNA testing for NF1.

Not routinely done - NF1 gene is VERY big, so testing takes too long

14

List the 3 main symptoms of Duchenne muscular dystrophy.

What is the age of onset for DMD?

Muscle weakness
Diminished muscle tone and reflexes
Death by respiratory failure in late teens/early 20s

Age of onset: childhood

15

What type of inheritance does DMD follow?

Describe the genetic basis of DMD. (2)

X-linked recessive

GENETIC BASIS:
1. DMD gene is found on the small arm of the X chromosome (Xp21)
a. Codes for the protein dystrophin, which normally links the internal cytoskeleton to the ECM by linking F-actin and the dystroglycan complex

2. Therefore, mutated proteins can't link the cytoskeleton and ECM, causing severe structural weaknesses

16

Other than DNA testing, how can you test for DMD?

Serum creatinine kinase: increased (because creatinine kinase leaks out of damaged muscles)

17

List the main symptom of fragile X syndrome.

Severe learning disabilities

18

What sort of inheritance does fragile X syndrome follow?

Describe the genetic basis of fragile X syndrome. (3)

X-linked recessive inheritance with genetic anticipation

GENETIC BASIS:
1. CGG repeats in the 5' region of the FMR1 gene

2. Mutation causes switched off transcription of the gene, therefore no FMR protein is produced
a. FMRP is usually needed for neuronal development

3. May have some manifesting carriers

19

List 3 common trisomy conditions.

Trisomy 21 - Down's syndrome
Trisomy 18 - Edward's syndrome
Trisomy 13 - Patau's syndrome

20

List 3 complications of Down's syndrome.

Learning disabilities
Heart malformations
Hypothyroidism

21

List 4 symptoms of Edward's syndrome (trisomy 18).

What is the prognosis of this condition?

Small chin
Clenched hands with overlapping fingers
Malformation of heart/kidneys/other organs
Severe learning disabilities

Unlikely to survive past 1 year

22

List 5 symptoms of Patau's syndrome (trisomy 13).

What is the prognosis of this condition?

Cleft lip/palate
Microphthalmia
Abnormal ears
Clenched fits
Polydactyly

50% die within 1 month
Only 10% survive past 1 yo

23

What is the most common cause of trisomy disorders?

Maternal non-dysjunction at first meiotic division

Risk increases with maternal age (NOTE: not paternal age, though this increases risk of new mutations)

24

Define "balanced translocation".

Translocation of DNA between two chromosomes which does not interrupt any genes or result in the loss/gain of any DNA; this will not cause disease

25

Define "unbalanced translocation".

Translocation of DNA between two chromosomes resulting in loss or gain of DNA; this can cause severe developmental disorders