Tuberous sclerosis Flashcards
What are the causes of tuberous sclerosis
- Genetic inheritance (autosomal dominant); majority of cases
- De-novo mutation; minority of cases
What do the non-mutated TSC-genes normally do?
The non-mutated TSC genes normally produce proteins that form a complex to inhibit mTOR. This inhibition is crucial to prevent excessive protein synthesis and uncontrolled cell growth.
Explain how TSC symptoms can be seen on the skin
o White spots (depigmentation) due to abnormal formation of cells
o Special kind of acne (small tumors)
o Benign growths on nails (fibromas)
o Benign growths at the level of the gums
o Fibrous plaques on forehead, …
Explain how TSC symtpoms can affect cognitive abilities
o Mental retardation
o Social communicative, language, attention, executive functions,memory
o Fine motor problems
Explain how TSC can cause behavioural problems
o Autism, ADHD, aggression, resistant to change
oNegativity, emotionally fragile, depressive episodes, anxiety disorders, sleep disorders, psychotic disroders related to epilepsy.
discuss the onset of symptoms of TSC
o Cardiac symptoms start early on, but they disappear
relatively quickly by themselves.
o Renal symptoms start early on and go on the age of 60.
o Cerebral early on into early adulthood (dangerous because
that’s a critical time for brain development)
o Skin symptoms start during puberty and leave at the age of 40.
o Lungs often from adult hood onwards.
epislepsy in TSC patients (percentages)
o Epilepsy in 90% of TSC patients
o 71% of patients develop seizures in the first 2 years of life.
How do we know the patient is having a seizure apart from looking at the body language?
An EEG
o An EEG picks up the electrical signals that are produced by the brain.
o During these epileptic seizures–we can’t see any sort of constant pattern in electrical signals–this means that there’s no structure in brain activity at all.
o During the time that these kids are having these seizures, they can’t learn anything new.
discuss individual differences of TSC patients
o How big the tumors are and where they’re located.
o Whether or not the tumors can be surgically removed.
o Different amount of attacks
o the same mutations can cause different gradations of TSC
What are the different types of epilepsies in TSC
- Epileptic spasms/Infantile spasms (West Syndrome)
- Focal epilepsy
- Symptomatic generalized epilepsy (Lennox Gastaut epilepsy)
discuss the diagnosis of TSC
Prenatal diagnosis is possible today, using ultrasound or MRI; detecting tumor (especially in heart; rhabdomyomas a lot of certainty for TSC)
o Discussion about abortion: there is also a chance that the child will have little or no problems with TSC
Age at diagnosis is often very early (20% even antenatal(before birth), the rest mainly in the first year of life;
then treatment is certainly still possible, but will in any case have less effect than if from birth)
Discuss the treatment of TSC
- Ketogenic diet can sometimes help against epilepsy.
- mTOR inhibitors (e.g., everolimus)
- Study: strong decrease and significant difference with placebo group; but poor decrease to 50%
- Declaration: pts already 2 years at the start of treatment; the earlier, the greater the effect!
What does autosomal dominant mean
o Autosomal = the gene in question is located on one of the non-sex chromosomes
o Dominant=a single copy of the mutated gene is enough to cause the disorder.
what does de-novo mutation mean
Fertilization mutations, in child itself
what are the 2 most common mutations of TSC
o Chromosome 9, TSC1 gene
o Chromosome 16, TSC2 gene (MORE SERIOUS)
what;s the incidence rate of TSC
1/6000
Without inhibition by the TSC complex ….
… mTOR activity remains unchecked, leading to excessive protein synthesis and cell growth. This can result in abnormal tissue growth and the formation of tumors, which is characteristic of TSC.
fibromas
benign growths on nails
Epileptic spasms/ infantile spasms (West syndrome)
The seizures look like a sudden bending forward of the body with stiffening of the arms and legs for one or two seconds – They often happen in many clusters, with hundreds of seizures a day.
Focal epilepsy
They are characterized by seizures arising from a specific part (lobe) of the brain.
Symptomatic generalised epilepsy (Lennos Gastaut epilepsy)
A type of epilepsy with multiple different types of seizures, particularly tonic (stiffening) and atonic (drop) seizures.
o Difficult to treat, especially with TSC patients.
discuss mtor inhibitors as treatment against TSC
they inhibit mTOR pathways, the tubers become smaller and epilepsy decreases
