Common Genetic Disorders Flashcards
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
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
- 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) - 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
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
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
What sort of inheritance does myotonic dystrophy follow?
Describe the genetic basis of myotonic dystrophy. (4)
Autosomal dominant inheritance with genetic anticipation
GENETIC BASIS:
- 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 - Normally, splicing factors (e.g. muscleblind proteins) are proteins needed to splice other genes
- 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 - This cause indirect toxic effects on other genes, e.g.
a. CLCN1 gene: chloride ion channel (causing myotonia)
b. Insulin receptors (causing diabetes)
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
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
What type of inheritance does CF show?
Describe the genetic basis of CF. (3)
Autosomal recessive inheritance
GENETIC BASIS:
- 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 - This means that chloride (and therefore water) cannot leave the cells
a. This causes secretions with increased thickness - This results in recurrent lung infections and pancreatic insufficiency, among other problems
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
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
List 6 (rare) complications of neurofibromatosis 1.
Hypertension Scoliosis Tibia fractures Phaeochromocytoma Sarcoma Optic pathway glioma
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:
- NF1 gene codes for neurofibronin, which normally inhibits RAS proteins in the RAS signalling pathways
a. Therefore inhibits the cell cycle - Therefore mutation in NF1 causes continuous activation of the cell cycle
a. This leads to several types of cancer
Describe DNA testing for NF1.
Not routinely done - NF1 gene is VERY big, so testing takes too long
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
What type of inheritance does DMD follow?
Describe the genetic basis of DMD. (2)
X-linked recessive
GENETIC BASIS:
- 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 - Therefore, mutated proteins can’t link the cytoskeleton and ECM, causing severe structural weaknesses
