8: Genetics - tuberous sclerosis, epidermolysis bullosa, NF type 1 Flashcards
What is the biggest factor contributing towards your chance of having a mutation?
Age of the father
A patient presents with periungual fibromata and longitudinal ridging in their toenails.
What is a periungual fibroma?
What genetic condition do they have?
Small lesions found at the nail folds
Tuberous sclerosis
What is an early neuro sign that a person may have tuberous sclerosis?
Infantile seizures
What is the mode of inheritance for tuberous sclerosis?
Autosomal dominant
Can tuberous sclerosis develop spontaneously in an adult? If so, why?
Yes
Spontaneous mutation
Mutations in which genes are responsible for tuberous sclerosis?
TSC1
TSC2
What type of genes are TSC1 and TSC2?
Tumour suppressor genes
Which specific proteins do TSC1 and TSC2 code for?
TSC1 - hamartin
TSC2 - tuberin
What is the earliest cutaneous sign of tuberous sclerosis?
Ash-leaf macules
Which piece of equipment can be used to better visualise ash-leaf macules?
Wood’s lamp
What are ash-leaf macules?
Depigmented macules which look like trees
What are facial angiofibromas?
Brown lesions on the face
Cortical tubers are another sign of tuberous sclerosis. What can they cause?
Seizures
What are hamartomas?
Where can they be found in tuberous sclerosis?
Benign growth malformations which resemble neoplasms
Heart, lungs, kidneys
What happens to the tooth enamel in tuberous sclerosis?
Pitting
What are Shagreen patches?
Where are they found?
Connective tissue lesions which look like orange peels
Lower back
Name five signs of tuberous sclerosis.
Seizures
Ash-leaf macules
Periungual fibromas
Facial angiofibromas
Cortical tubers
Hamartomas
Shagreen’s patches
Pitting of tooth enamel
Bone cysts
Autosomal dominant conditions are seen in (all / some) generations.
all generations
If a parent is affected by an autosomal dominant condition, what are the chances of their child inheriting it?
50%
What two characteristics of autosomal dominant conditions are variable?
Expressivity (whether it is severe or not)
Penetrance (whether it presents or not)
Are males and females equally likely to inherit an autosomal dominant condition?
Yes
During transcription, (introns / exons) are removed from DNA.
introns
(Introns / exons) are vital for RNA and protein expression.
Exons
Which experimental drugs may be used to treat tuberous sclerosis?
mTOR inhibitors
Tuberous sclerosis shows genetic heterogeneity. What does that mean?
The mutation can be in either TSC1 or TSC2 and the disease will still present itself
Some people have the mutation but don’t show features of the disease at all - its ___ is variable.
Tuberous sclerosis has varying severity in different people - its ___ is variable.
penetrance
expressivity
Is tuberous sclerosis a:
Mendelian disorder (with high penetrance but low frequency)
or a Multifactorial disorder (with low penetrance but high frequency)?
Mendelian disorder
What is epidermolysis bullosa?
A group of genetic skin fragility conditions
Causes skin loss and blistering on gentle handling of patient
Is epidermolysis bullosa autosomal dominant or recessive?
All of the above
can also be acquired via a new mutation
What is the presentation of epidermolysis bullosa?
Widespread blistering and skin shedding on slight handling of skin
What are the three types of epidermolysis bullosa, and which layers of the skin are affected?
Simplex - epidermis only
Junctional - dermo-epidermal junction
Dystrophic - all the way to the dermis
How many faulty genes are involved in epidermolysis bullosa?
> 10 genes (probably 20 now)
The genes for which protein families are faulty in epidermolysis bullosa?
Keratin
Collagen
Integrins
The faulty genes in epidermolysis bullosa are usually responsible for skin ____ and ___.
structure and adhesion
What is epidermolysis bullosa aquisita?
Rare autoimmune condition similar to EB
What is haploinsufficiency?
Mutant gene doesn’t produce any protein, meaning only half as much protein is produced
What is dominant negative disease expression?
Mutant gene causes production of abnormal protein, which interferes with normal protein
A mutation in a gene for protein can cause that protein to gain new ___.
Which disease type is this important in?
function
Cancer
If a disease is autosomal recessive, how much protein will be produced?
None
oops
How many generations are affected by autosomal recessive conditions?
Usually only one
If a parent has an autosomal recessive condition, what is the chance of their child inheriting it?
25%
The chance of children inheriting autosomal recessive conditions is increased in families which are ___.
consanguineous
i.e inbreeding
What is the name given to round, flat coffee-coloured marks on the skin which are asymptomatic?
Cafe au lait macules
Cafe au lait macules are found on 10-20% of normal people. More than how many suggests that a person has a genetic disease?
More than 5
What is a neurofibroma?
Benign nerve sheath tumour found on the SKIN - brown, soft, papular
If a patient presents with more than 5 cafe au lait macules and neurofibromas, which genetic skin condition do they have?
Neurofibromatosis type 1
What is the mode of inheritance of neurofibromatosis type I?
Autosomal dominant
Apart from Cafe au lait macules and neurofibromas, what are some other signs of neurofibromatosis type I?
Axillary / inguinal freckling
Optic gliomas (eye tumours)
Bony lesions
Which drugs may be used to treat neurofibromatosis type I in the future?
MEK inhibitors
Most diseases (are / aren’t) caused by one gene.
aren’t
Which skin disease, causing itchy skin and difficulty sleeping in infants, also has genetic contributing factors?
Atopic eczema
A loss-of-function mutation in which gene is thought to cause atopic eczema?
Filaggrin gene
Filaggrin mutations cause which disease?
Ichthyosis vulgaris
dead skin cells don’t shed, causing dry, itchy skin
What is filaggrin an abbreviation for?
Filament aggregating protein
The dark purple colour of which epidermal layer is lost in ichthyosis vulgaris?
Granular layer
Mutations in the filaggrin gene increase your risk of which atopic conditions?
Eczema
Asthma
Hayfever
Peanut allergy
